M&R Session 8 (Lecture 8.1 + 8.2)

Question 1

What is the formula for molarity (M) ?

Answer 1

Molarity (M) = g/L / MWt

Question 2

How do most drugs bind to receptors?

Answer 2

Reversibly

Question 3

What law does binding of drugs obey?

Answer 3

Law of mass action (related to concentrations of reactants & products)

Question 4

What is drug action dictated by?

Answer 4

Affinity and intrinsic efficacy

Question 5

What does an agonist have?

Answer 5

A ligand that causes a response

With both affinity and intrinsic efficacy

Question 6

What is the difference between intrinsic efficacy and efficacy?

Answer 6

Intrinsic eff - ability for ligand to produce the AR*

Eff - Cell/tissue dependant factors that determine a response

Question 7

What does an antagonist have and do?

Answer 7

Affinity ( NO INTRINSIC EFFICACY)

Block the effects of agonists i.e. prevent receptor activation by agonists

Question 8

What is Bmax?

Answer 8

Maximum binding capacity - info about receptor no.

Question 9

What is Kd and what type of graph can this be obtained from?

Answer 9

Kd = dissociation constant ( a measure of affinity) - concentration of ligand required to occupy 50% of the available receptors
From proportion of bound receptors vs [Drug] log10 nM

Question 10

A lower Kd value indicates?

Answer 10

Higher affinity

Question 11

What does -9log10 mean?

Answer 11

10-9 nM or 1nM

Question 12

What responses are induced by a drug? (2 general points)

Answer 12

Change in a signalling pathway

Change in cell or tissue behaviour (e.g. contraction)

Question 13

What can be obtained from a concentration - response curve?

Answer 13

EC50 and Emax

Question 14

What is Emax and EC50?

Answer 14

Emax - Effect maximum

EC50 - Effective concentration giving 50% of the maximal response

Question 15

What is the difference between concentration and dose?

Answer 15

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

Dose - [] at site of action unknown e.g. in patient

Question 16

What is a measure of potency and what does it depend on?

Answer 16

EC50

Depends on agonist affinity and intrinsic efficacy and efficacy

Left shift = more potent

Question 17

What factors affect the ‘making’ of a drug in clinical practice?

Answer 17

Affinity
Efficacy
Selectivity 
PK
Physicochemical properties e.g. solubility, pH, stability

Question 18

What is the problem with IV drip salbutamol?

Answer 18

Activates beta 1 and beta 2 receptors which can cure asthma by opening up airways (b2) but causes tachycardia and angina by activating b1 receptors on the heart

Question 19

What property of cells allows <100% occupancy but generate 100% response?

Answer 19

Spare receptors

(Find that response curve is left shifted to binding curve) i.e. EC50 < Kd so that 50% binding causes 100% response

Question 20

Why do spare receptors exist?

Answer 20

Amplification in the signal transduction pathway

Response limited by a post-receptor event

Question 21

What do spare receptors increase?

Answer 21

Sensitivity - allow responses at low concentrations of agonist ([drug] below Kd)

Question 22

How can changing the receptor number change the maximal response of a drug?

Answer 22

More receptors = lower [drug] for full response

Less receptors = if lower than Kd then 100% occupancy but insufficient receptors for full response

Question 23

When do receptor numbers change?

Answer 23

Increase with low activity

Decrease with high activity

Question 24

What are partial agonists and comment on their potency compared to full agonists?

Answer 24

Drugs that cannot produce a maximal effect, even with full receptor occupancy

PA can be more or less potent than full agonists.

PAs can act as an antagonist of a full agonist

Question 25

Describe the clinical use of partial agonists?

Answer 25

Opioids : Pain relief, Recreational use (heroin) - euphoria
BUT respiratory depression

Acts via Mu opioid receptor GPCR

Give buprenorphine which has a higher affinity but lower efficacy than morphine&raquo_space;> gives adequate pain control, less resp depression and stops other opioids from binding to receptors

Question 26

How can a partial agonist be changed?

Answer 26

By changing the number of Rs on a cell - from PA to FA.

PA still has low intrinsic efficacy at each receptor but there are sufficient receptors to contribute a full response

Question 27

Describe reversible competitive antagonists?

Answer 27

Relies on a dynamic equilibrium between ligands and receptors. Competitvely competes with agonist for binding site

Surmountable with increasing [agonist]

Cause parallel shift to the right in conc-resp curve

Question 28

What is IC50?

Answer 28

[Antagonist] giving 50% inhibition

Question 29

Give an example of a reversible comp antagonist and its clinical usage?

Answer 29

Naloxone - high affinity, comp ant at mu opioid receptors

Reversal of opioid-mediated resp depression- high affinity means it will compete effectively with other opioids for receptors.

Question 30

Describe irreversible competitive antagonism.

Answer 30

Occurs when the antagonist dissociates slowly or not at all.

Non-surmountable

Cause parallel shift to the right on conc-resp cuve and at higher [] suppress the maximal response

Question 31

Give an example of a irreversible comp antagonist and its clinical usage?

Answer 31

Phenoxybenzamine - non selec irr alpha 1 adrenoceptor blocker used in HT episodes in pheochromocytoma

Stops excessive vasoconstriction

Also clopidogrel (P2Y antagonist) so stops thrombosis

Question 32

Describe non competitive antagonism.

Answer 32

Drug binds to allosteric site affecting receptor orthosteric ligand affinity and/or efficacy

e.g. NMDA R for ketamine causing analgesia at low []s
reduced central excitation