M&R Factoids and Definitions

Question 0

Define Therapeutic Ratio

Answer 0

Maximum tolerated dose/minimum effective dose
OR
LD50/ED50

Question 1

Define Oral Bioavailability

Answer 1

Proportion of a dose given orally (or by any route other than IV) that reaches systemic circulation unchanged

Question 2

Define Volume of Distribution

Answer 2

Theoretical volume into which drug has distributed assuming that this occurred instantaneously

Question 3

Define Membrane

Answer 3

Continuous, selectively permeable barrier

Question 4

Define Receptor

Answer 4

A molecule that recognises specifically a second molecule (ligand) or family of molecules and in response to ligand binding brings about regulation of a cellular process

Question 5

Define ligand

Answer 5

Any molecule that binds specifically to a receptor site

Question 6

Define affinity

Answer 6

Likelihood of a ligand binding to a receptor

Or Strength of ligand-receptor interaction

Question 7

Activation of a receptor is governed by…

Answer 7

Intrinsic activity- measure of size of response

Question 8

Kd is…

Answer 8

Measure of affinity. Conc of ligand that causes 50% receptor occupancy. Reciprocal of affinity

Question 9

Bmax tells you about…

Answer 9

The maximum binding capacity (total number of receptors in a tissue)

Question 10

Efficacy is…

Answer 10

Intrinsic activity plus cell and tissue dependent factors. The difference between affinity and response curve- how well, once bound, the ligand produces a cellular response

Question 11

Affinity + efficacy is..

Just affinity is…

Answer 11

Agonist

Antagonist

Question 12

Emax is…

Answer 12

Maximum response of a particular agonist. Crude measure of efficacy

Question 13

EC50 is…

Answer 13

The effective concentration of ligand giving half the maximum response. Crude measure of potency

Question 14

Define Potency

Answer 14

Dose range over which a response is produced. Measured by EC50.
Depends on affinity and intrinsic activity/efficacy AND number of receptors

Question 15

If a tissue had reserve receptors, where would the response curve lie in relation to the binding curve?

Answer 15

To the left. EC50<Kd

Question 16

Define Partial Agonist

Answer 16

Binding, even at 100% occupancy cannot produce a maximum response. EC50=Kd 
System dependent (high number of receptors can covert to full agonist)

Question 17

Clinical use of affinity/efficacy

Answer 17

Salbutamol- poor affinity for B2 but high selective efficacy. Plus direct route of administration. (In high concs can increase HR)
Salmeterol- high affinity (so no need for selective efficacy)

Question 18

Clinical use of partial agonist

Answer 18

Opioids act on u opioid receptor (GPCR). Can cause resp depression.
Morphine (full agonist) can give pain relief but also RD. Buprenorphine (partial agonist) has higher affinity and lower efficacy- still provides adequate pain control, but less RD

Question 19

Why can giving Buprenorphine to a heroin addict (with heroin in their system) cause withdrawal symptoms?

Answer 19

Heroin in a full agonist. In high doses, Buprenorphine can act as a antagonist of heroin (efficacy is low but higher affinity so occupies receptor and limits response)- so can get withdrawal.
Therefore, partial agonists can act as antagonists of full agonists. (PA=mixed agonist/antagonist).
Buprenorphine can also be used in lower doses to enable gradual withdrawal from heroin.

Question 20

Higher dose (with same antagonist) or greater affinities (with differing antagonists) both cause…

(Reversible competitive antagonism)

Answer 20

Response curve of [agonist] shifts to the right

Question 21

Clinical example of reversible competitive antagonist

Answer 21

Naloxane- antagonist of u opioid receptors. Reverses resp depression

Question 22

What happens in irreversible competitive antagonism?

Answer 22

Antagonist dissociates very slowly/not at all - non surmountable.

Question 23

Clinical example of a irreversible competitive antagonist

Answer 23

Phenoxybenzamine- for pheochromocytoma. Irreversible a1 adrenoreceptor antagonist- good because even high adrenaline won’t outcompete it.

Question 24

Where do non competitive antagonists bind?

Answer 24

To the allosteric site of a receptor. Reduce the effect of agonist binding to the orthosteric site (decreased efficacy and/or affinity)

Question 25

Define Desensitisation

Define Tolerance

Answer 25

Desensitisation- when the effect of an agonist, when given continuously, is diminished as the tissue becomes less responsive. Develops over a few minutes.
Tolerance- more GRADUAL decrease in responsiveness

Question 26

Define Supersensitivity

Answer 26

Adaptive response in cells (in an attempt to overcome the drug effect) which may result in a ‘rebound’ effect in response to endogenous agonists when drug therapy ceases

Question 27

Define Homologous desensitisation

Answer 27

Only the receptor for the agonist that is signalling is desensitised

Question 28

Define Heterologous desensitisation

Answer 28

When receptors for several different agonists are desensitised when only one has been stimulated by an agonist

Question 29

Desensitisation of GPCRS can result from…

Answer 29

i) modification of the receptor by phosphorylation (most commonly associated with heterologous desen)
ii) reversible receptor internalisation (sequestered to a pool for later use when needed)
iii) down regulation (irreversible internalisation- to lysosome where agonist and receptor are degraded)