Drugs and Receptors

Question 1

What are some common drug targets (generally)?

Answer 1

Most drugs bind reversibly (association and dissociation) proteins, such as: enzymes, GPCRs, ion channels, transporters etc. However some might bind to DNA, such as antitumour drugs.

Question 2

What is the importance of the concentration of drug molecules?

Answer 2

The concentration of a drug is critical in determining the drug action. Drugs of equivalent molecular weights will have the same concentration; however, at a given weight, drugs with different molecular weights will have different concentrations

1 mole contains 6 x 10^23 particles

Question 3

How would you calculate grams per Litre?

Answer 3

molecular weight x Molarity = grams per Litre

Question 4

How can you calculate Molarity?

Answer 4

Grams per Litre/ molecular weight

Question 5

What is meant by the terms intrinsic efficacy and affinity?

Answer 5

Agonists bind to receptors and cause a response, therefore they have both affinity and intrinsic efficacy. Antagonists bind but elicit no response. They are said to have affinity but no intrinsic efficacy.

Question 6

What two factors determine drug action?

Answer 6

Affinity and intrinsic efficacy

Question 7

What is the difference between efficacy and intrinsic efficacy?

Answer 7

Intrinsic efficacy is a drugs ability to induce a conformational change in a receptor, i.e. to activate it. Efficacy describes the cells subsequent response to that change or activation, i.e. the cellular response.

Question 8

How can we quantify binding of a drug?

Answer 8

This is usually done using radioactively labelled ligands. The maximum binding capacity, Bmax, indicates the total number of receptors. The dissociation constant, Kd, indicates the concentration of drug needed to fill half of the receptors. Therefore Kd is a measure of AFFINITY.

Question 9

What is EC50 and what does it indicate?

Answer 9

Effective Concentration giving 50% of the maximal response. This is a measure of POTENCY and can be calculated by combining intrinsic efficacy and affinity.

Question 10

Discuss affinity and efficacy in relation to beta adrenoceptors

Answer 10

In asthma, we want to stimulate beta2 receptors to induce bronchodilation. However, not all drugs bind to this receptor exclusively. Therefore we have to find drugs with a high affinity for the receptor we want, but a low affinity for others.

salbutamol has a Kd for B1 receptors of 20 microM, and of 1 microM for B2, therefore has a higher affinity. It also has selective efficacy.

Salmeterol does not have selective efficacy, but it does have highly specific affinity. 1900nm compared to 0.55 nm.

Question 11

What are spare receptors?

Answer 11

Spare receptors are said to occur when we have 100% response, with less than 100% binding of receptors. This is because of signal amplification. Spare receptors therefore increase sensitivity, allowing for responses even with low agonist concentration.

Question 12

What is the difference between a full and partial agonist?

Answer 12

Partial agonists are those which do not produce a full response despite 100% binding. Full agonists produce a full response with 100% binding.

Partial agonists have a EC50 equal to their Kd. They may also have higher affinity and efficacy, making them more potent than their full agonist counterparts.

However, depending on which tissues and where in the body we are looking, a partial agonist in one location may be a full agonist in another.

Question 13

What is the difference between a full and partial agonist?

Answer 13

Partial agonists are those which do not produce a full response despite 100% binding. Full agonists produce a full response with 100% binding.

Partial agonists have a EC50 equal to their Kd. They may also have higher affinity and efficacy, making them more potent than their full agonist counterparts.

However, depending on which tissues and which receptors we are looking at, partial agonists may not always be partial agonists!

Question 14

What are the clinical uses of partial agonists?

Answer 14

We can use partial agonists to get around the harmful overdose effects of some drugs. For example, morphine in high doses may cause respiratory depression. Buprenorphine, however, has a higher affinity but a lower efficacy. This means that it can be used to control pain without as much respiratory depression, or to block opioid receptors in drug rehabilitation.

In this way, the partial agonist is acting as an antagonist of the full agonist.

Question 15

What are the three main types of antagonists?

Answer 15

1. Reversible competitive antagonist
2. Irreversible competitive antagonist
3. Non-competitive antagonise

Question 16

Explain reversible competitive antagonists

Answer 16

Reversible competitive antagonists compete with agonists in the dynamic equilibrium seen at receptor sites. This means that you can outcompete an agonist with an antagonist, or vice versa. A clinical example is Naloxone, which outcompetes opioids at micro-opioid receptors.

Question 17

Explain irreversible competitive antagonists

Answer 17

Irreversible competitive antagonists are slow to dissociate from receptors, if at all. This means that to elicit the same response, more agonist is required. These bind to the spare receptors. When spare receptors are occupied by ICA then this can suppress the maximum response. A clinical example is phenoxybenzamine, used in pheochromocytoma, where it blocks adrenoceptors and prevents hypertension.

Question 18

Explain non-competitive antagonists

Answer 18

Non competitive antagonists bind to the receptor allosterically. They reduce the maximal response and cannot be outcompeted by agonists.

Question 19

What is molarity?

Answer 19

Molarity is the concentration of a solution expressed as the number of moles of solute per litre of solution