Amount of receptor that is bound by a given concentration of drugHow tight the drug-receptor complex it

Relationship between the amount of receptor occupied by drug and the size of the responseThe maximum response measured when all receptors are occupied with drug

Antagonist concentration needed to reduce agonist response by 50%This is not constant (↑ [agonist] → ↑ IC₅₀)

Affinity constant↑K₁ → ↑ affinity of drug to receptorUnits = M⁻¹

Dissociation constant (K₁=1/Kd)Units = MKd = concentration of drug that gives half the maximum occupancy

1.0 Drug Receptor Interactions Flashcards by Toby Charles

What forces are involved in binding ligand to receptor? (stronger to weakest)

1) Covalent 2) Ionic 3) H-bond 4) Van der Waals 5) Hydrophobic

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What is an agonist?

Binds to a receptor and generates a response

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What is an antagonist?

A drug which opposes the action of an agonist drug Competitive = same binding site. No efficacy Non-competitive - Different mechanisms 1) Binds to allosteric site → ↓ agonist binding 2) Irreversible binding to same site 3) A drug that activates another pathway → opposing the effect of agonist (functional non-competitive agonist)

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Define affinity

Amount of receptor that is bound by a given concentration of drug How tight the drug-receptor complex it

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Define dissociation

How readily the drug unbinds

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Define affinity constant

Inverse of the concentration of drug needed to occupy half the receptors

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What are the equations for affinity constant?

1) K+1/K+2 2) 1/Kd

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Define efficacy

Relationship between the amount of receptor occupied by drug and the size of the response The maximum response measured when all receptors are occupied with drug

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Define EC₅₀

Concentration of drug that leads to 50% of maximal response

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Define potency

Potency refers to the concentration of a drug causing a particular magnitude of response (e.g. EC₅₀) Combination of affinity and efficacy

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Define selectivity

A drug is selective for a particular receptor if it has a high affinity for one particular receptor type and low affinity (if any) for others

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Define IC₅₀

Antagonist concentration needed to reduce agonist response by 50% This is not constant (↑ [agonist] → ↑ IC₅₀)

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Name an agonist and antagonist for muscarinic and nicotinic receptors:

Muscarinic Agonist = Muscarine Antagonist = Atropine Nicotinic Agonist = Nicotine Antagonist = d-tubocurarine

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What is Ka?

Affinity constant ↑K₁ → ↑ affinity of drug to receptor Units = M⁻¹

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What is Kd?

Dissociation constant (K₁=1/Kd) Units = M Kd = concentration of drug that gives half the maximum occupancy

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What is K₂?

Affinity constant for antagonist

What is pA₂?

Log(K₂) The concentration of antagonist needed to shift EC₅₀ across 2 fold = 10^pA₂

What is the formula for fraction of receptors bound?

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What makes up total binding of a drug?

1) Specific binding - Binding to receptor - Saturable 2) Non-specific binding - Binding to sites away from receptor - Linear and non-saturable

What is the spare receptor (receptor reserve) concept?

Only a fraction of the receptors are needed to produce a maximum response In these situations Kd&raquo_space; EC₅₀

What is the significance of receptor reserve?

1) Allows lower concentrations of drug/molecule to cause effect (this is useful as agonists can therefore be low affinity, meaning that their effect has rapid onset and offset) 2) Maximum response can still be achieved despite some loss of receptors through desensitisation/ antagonism

Give some reasons why EC₅₀ and Kd are not the same:

1) Receptor reserve 2) Response may occur before drug-receptor binding interaction reaches equilibrium 3) Response may occur due to >1 pathway 4) Concentration of drug bathing tissues may be different to concentration of drug reaching receptors

How long does nACh channel open for when agonist binds?

1ms (allowing 10,000 Na⁺ to enter)

What are the subunits of nACh?

α x 2 β γ δ Each subunit has M1-M4 stretches. M2 from each unit lines the pore

What is receptor desensitization?

Prolonged exposure to an agonist → receptors are prevented from producing their normal effect (transduction mechanism is uncoupled)

Desensitisation may include a change in drug affinity or a change in number of receptors (or both)

What are the mechanisms of desensitization in β₂ adrenoreceptor?

1) Uncoupling
Seconds → minutes
a) Heterologous desensitization (PKA)
b) Homologous desensitization (βARK)

2) Sequestration
Minutes
Receptors taken up by endocytosis

3) Downregulation
Minutes → hours
PKA alter mRNA stability → ↓ receptors

How many membrane spanning segments do voltage gated ion channels have?

4 groups of 6 membrane spanning segments
(Na⁺ + Ca²⁺ channels = one polypeptide, K⁺ channel = 4 polypeptides)

What are the three Na⁺ channel conformations?

1) Open
2) Closed
3) Inactive/refractory

What fibres are preferentially targetted by LAs?

Aδ +C

What is use-dependence?

Rate of channel block is dependent on the rate at which the nerve is stimulated

What is voltage dependence?

Rate of channel block is faster if more channels open (Pre-pulse depolarisation causes faster nerve block than pre-pulse hyperpolarisation)

What is the pKa of lidocaine?

8-9

How does benzocaine enter the cell?

Non charged, therefore enters the cell using hydrophobic pathway

How does lidocaine enter the cell?

1) Binds to and stabilises the inactive conformation of the channel
2) Crosses membrane in uncharged form
3) Blocks channel in charged form
4) Shows use dependence + voltage dependence

Give three types of Ca²⁺ channel:

1) L-type
2) T-type
3) N-Type

What are the three different responses to depolarisation (modes) that L-type calcium channels show?

Mode 1 - channel opening is in bursts followed by long closed intervals
Mode 2 - Very long openins
Mode 0 - Channel doesn't open