M&R Session 8 Flashcards by Charlotte Manton

What equation is used to calculate molarity?

Grams per litre/molecular weight

How well did you know this?

Not at all

Perfectly

Which drugs do not bind to proteins?

Anti microbial

Anti tumour

How well did you know this?

Not at all

Perfectly

Why must drug concentrations be considered in molarity?

Using equal weights of substances w/ different molecular weights leads to different concentrations of molecules

How well did you know this?

Not at all

Perfectly

What is the critical determinant of drug action?

The molarity of drug molecules around receptors

How well did you know this?

Not at all

Perfectly

What law does drug binding obey?

Mass action

How well did you know this?

Not at all

Perfectly

What forms the dynamic equilibrium between ligand, receptors and the complex they form upon binding?

Association and dissociation

How well did you know this?

Not at all

Perfectly

What is related to the binding of drug molecules to receptors?

[reactants]
[products]
Le Chatelier’s principle

How well did you know this?

Not at all

Perfectly

What two characteristics do agonists have?

Affinity

Intrinsic efficacy

How well did you know this?

Not at all

Perfectly

What governs receptor activation to give intracellular effects?

Intrinsic efficacy

How well did you know this?

Not at all

Perfectly

What is intrinsic efficacy?

The ability to turn a receptor on by forming an activated receptor

How well did you know this?

Not at all

Perfectly

What is efficacy?

Ability to cause coupling leading to cellular action

Ability to generate a biological response

How well did you know this?

Not at all

Perfectly

What determines efficacy?

Cell/tissue-dependent factors

How well did you know this?

Not at all

Perfectly

Why can an antagonist not cause a response?

It only has affinity so cannot convert the receptor to an active form - no conformational change

How well did you know this?

Not at all

Perfectly

How do antagonists prevent receptors being turned on?

Prevent agonist binding

How well did you know this?

Not at all

Perfectly

What two methods are used to measure drug-receptor interactions?

Binding w/radioligand

Relation b/w [drug] and response

How well did you know this?

Not at all

Perfectly

Describe the process of radioligand binding.

Bind radioligand to cells/prepared membranes –> separate bound and free radioligand –> low [ligand] = low binding,

How well did you know this?

Not at all

Perfectly

What is B(max)?

The concentration at which all receptors are full

How well did you know this?

Not at all

Perfectly

What is Kd?

The dissociation constant = 50% occupancy

Measure of affinity

How well did you know this?

Not at all

Perfectly

Is Kd affected by receptor number?

Nope

How well did you know this?

Not at all

Perfectly

What does a low Kd indicate?

High affinity

How well did you know this?

Not at all

Perfectly

What is K(A)?

Index of affinity determined by functional assay

How well did you know this?

Not at all

Perfectly

What is the definition of a logarithm?

The exponent by which a fixed (base) value has to be raised to give a particular number

How well did you know this?

Not at all

Perfectly

How is [drug] usually expressed?

On a logarithmic scale giving a sigmoidal curve

How well did you know this?

Not at all

Perfectly

Can Kd be used for agonists and antagonists?

Yes, it can be used for any type of ligand

How well did you know this?

Not at all

Perfectly

What does receptor response require?

Efficacy

What type of ligand must be used to measure drug-receptor interactions by relation b/w [drug] and response?

An agonist

What is E(max)?

Effect maximum; a tissue can only secrete/contract so much

What is EC50?

Effective concentration giving 50% of the maximal response

Define concentration in relation to drug action.

Known [drug] at site of action e.g. in cells and tissues

Define dose.

Concentration at an unknown site of action e.g. dose to a patient (mg or mg/kg)

What is potency?

How good a drug is at generating a biological response

What does potency depend on?

Affinity Intrinsic efficacy Efficacy

What is the key determinant of efficacy?

The number of receptors present

What factors must be considered in drug action?

``` Affinity Efficacy Selectivity Pharmacokinetics Physiochemical properties ```

What is the therapeutic target used in asthma treatment?

Beta 2-adrenoreceptors

Why do agonists for asthma treatment need to have specificity rather than just their usual high selectivity?

So they do not act on beta 1-adrenoreceptors in the heart

What is functional antagonism?

Where the antagonist of the action not the receptor

How is Salbutamol utility increased?

Beta 2-selective efficacy | Route of administration

Describe the action of Salbutamol.

Binds slightly preferentially to beta 2 and is particularly good at turning beta 2 on

Describe the action of Salmeterol.

Long acting | Selectivity based on affinity as it has no selective efficacy

What problems are associated with Salbutamol and Salmeterol respectively?

Salbutamol: can act on beta 1-adrenoreceptors in heart --> increases HR --> angina (common in elderly w/asthma) Salmeterol: insoluble so cannot be given IV when nebuliser no longer an option

When are spare receptors often seen?

When receptors are catalytically active

Give two examples of receptor types you would expect to see spare receptors with.

Tyrosine kinase | GPCRs

Why do spare receptors exist?

B/c of amplification and response limited by post-receptor event

In asthma what percentage of M3 muscarinic receptors are activated to give maximal contraction?

10%

Describe the relationship b/w drug concentration and its Kd if there are no spare receptors.

For full receptor response requires >> Kd of drug

What effect do spare receptors have on sensititvity?

Increase

Describe the response when there are spare receptors present.

Occurs at lower [agonist] Occurs at Kd Decreased [drug] for full response

What does changing receptor number do?

Changes agonist potency | Can affect the maximal response

Describe the relationship b/w [drug], its effects and receptor number.

Same [drug] has different effects depending on receptor number

What happens if receptor number is low?

There is 100% occupancy but insufficient receptors for a full response

What can cause up-regulation of receptors w/low activity and down-regulation w/high activity?

Physiological, pathological or drug-induced changes

What is tachyphylaxis?

Desensitised receptors

How can partial agonists not elicit maximal response with full receptor occupancy?

Insufficient efficacy creates a different activated receptor so it is turned on but not fully

What tends to happen with the binding curve and function curve for a partial agonist?

Overlap so EC50 ~ Kd

What type of receptors do opioids primarily bind to?

Mu-opioid

Why is buprenorphine sometimes used clinically instead of morphine?

It has a higher affinity but lower efficacy so can give sufficient pain control with a lower risk of breathing depression

What type of agonist is heroin?

Full

Which mixed agonist/antagonist is used to aid heroin withdrawal?

Buprenorphine

What can cause a partial agonist to act as a full agonist?

Increased receptor number (low efficacy but enough receptors --> full response)

What indicates intrinsic activity?

Maximal response

Can full agonists w/identical intrinsic activities have different efficacies?

Yes

What can be said about the response of two full agonists with equal intrinsic activity?

They have the same maximum response

In which direction does the response curve of a drug move with increasing potency?

Left

What does reversible competitive antagonism rely on?

A dynamic equilibrium b/w ligands and receptors

What is K50?

The concentration of antagonist which gives 50% inhibition | Index of antagonist potency determined by [agonist]

What is the difference between Kd and KB?

``` Kd = antagonist affinity derived from radioligand KB = antagonist affinity derived pharmacologically ```

How do reversible competitive antagonists affect agonist concentration-response curves?

Cause parallel shift to right

Which drug can be used clinically to reverse opioid-mediated respiratory depression?

Naloxone

When does irreversible competitive antagonism occur?

When the antagonist dissociates slowly or not at all

How does irreversible competitive antagonism affect the agonist concentration-response curve?

Parallel shift to right and suppresses maximal response

How does irreversible competitive antagonism suppress maximal response?

Spare receptors are filled by antagonist therefore there are insufficient receptors for a full response

How does phenoxybenzamine work?

Non-selective alpha 1 adrenoreceptor blocker that binds covalently so no matter how much adrenaline/NA present vasoconstriction is not caused

What mechanism of action does Clopidogrel use to prevent thrombosis?

Irreversible P2Y12 antagonist which prevents cytochrome P450 metabolism

What is non-competitive antagonism?

Endogenous ligand binds to orthosteric site on extracellular part of GPCR

What are allosteric sites?

Binding sites for agonists and molecules that enhance or reduce ability of endogenous ligand to turn receptor on

What type of antagonism does non-competitive antagonism resemble when comparing [agonist]-response curve?

Irreversible competitive antagonism

Describe an NMDA (excitatory glutamate) receptor.

Inotropic receptor Ligand gated ion channel Distinct glutamate and ketamine binding sites

What effects can binding at an NDMA produce?

Analgesia | Decreased central excitation

Describe the allosteric sites of GPCRs.

High specificity | High receptor subtype selectivity

Are GPCRs competitive?

What do GPCRs often require to function?

Orthosteric ligand