Full agonist, partial agonist and inverse agonist

Question 1

Define agonist

Answer 1

A ligand that binds to a receptor and alters the receptor state resulting in a biological response

Question 2

Define full agonist

Answer 2

A full agonist reaches the maximal response capability of the system.

Full agonists have intrinsic activity at the receptor of 1.

Question 3

Define intrinsic activity

Answer 3

It is the efficacy of the drug

It refers to the magnitude of effect the drug has once bound

It refers to the relative ability of a drug-receptor complex to produce a maximum functional response

Intrinsic Activity takes values between 0 and 1.

Inverse agonists can have intrinsic activity of -1 to 0

Question 4

Define a partial agonist

Answer 4

A partial agonist does not reach the maximal response capacity of the system even at full receptor capacity

Question 5

What is an inverse agonist. Give two examples.

Answer 5

These are ligands that induce the opposite effect to that of the endogenous agonist.

By binding to its receptors, an inverse agonist, reduces the fraction of receptors in the active formation so reducing the action of the endogenous ligand

Examples:

1. Carvedilol
2. Antihistamines (H1 and H2 receptor blockers)

Question 6

Define affinity

Answer 6

Affinity refers to how well or avidly a ligand binds to its receptor

Question 7

Define the intrinsic activity of the following ligand types

1. Full agonist
2. Antagonist
3. Partial agonist
4. Inverse agonist

Answer 7

1. Full agonist: IA = 1
2. Antagonist: IA = 0
3. Partial agonist: 0 < IA < 1
4. Inverse agonist: -1 < IA , 0

Question 8

Define an antagonist

Answer 8

Exhibit affinity but no intrinsic activity at the receptor. Their binding may be reversible or irreversible

Question 9

Classify and define reversible antagonists. Give one example of each

Answer 9

Competitive and non-competitive

Competitive antagonist effect may be overcome by increasing the concentration of the agonist - the two molecules compete for the same site and the relative concentration of each determines receptor occupancy
E.g. Ach and NDMR at nicotinic receptors in NMJ.

Non-competitive

Do not bind to the same site of the agonist. Classically, they do not alter binding of the agonist. Their antagonism results from preventing receptor activation through conformational distortion
E.g. ketamine (antagonises glutamate at NMDA receptors inn CNS)

Question 10

What is allosteric modulation. What types exist and give one example

Answer 10

Not all drugs with reversible activity fit neatly into the competitive and non-competitive categories.

Allosteric modulators are drugs that bind distant from the agonist receptor site , yet still alter the BINDING CHARACTERISTICS of the agonist.

–> Positive allosteric modulators: increase activity of given dose of agonist without having any intrinsic activity of their own
E.g benzodiazepines at GAVAa receptor

–> Negative allosteric modulator: reduce activity of a given dose of the agonist without having any discernible effects of their own

Question 11

What is an irreversible antagonist. Give 2 examples

Answer 11

Bind and irreversibly block the receptor at either the binding site or at a distant site. increasing concentration of agonist will not overcome the blockade.
E.g.
1. Phenoxybenzamine (alpha 1 adrenereceptor blocker)
2. Clopidogrel (Platelet ADP receptor blockade)

Question 12

Define tachyphylaxis.Give example of drug

Answer 12

Rapid decrease to the response to repeated doses over a short period of time

(decrease of stores of transmitter before resynthesis can take place)

E.g. Ephidrine

Question 13

Define desensitization

Answer 13

Chronic loss of response over a longer period of time caused by structural damage in receptor morphology or by an absolute loss of receptor numbers

E.g. Loss of B adrenergic receptors from the myocardial surface in the continued presence of adrenalin and dobutamine

Question 14

Define tolerance

Answer 14

Larger doses are required to produce the same pharmacological effect

E.g. Chronic opioid abuse

Reflects altered sensitivity of the CNS to opioids

Mechanism: reduction in receptor density or affinity

E.g

1. Opioids
2. Nitrates (wait overnight for replenishment of sulfhydryl groups on VSM)

Question 15

how can a partial agonist act as an antagonist

Answer 15

When it is given at the same time as the full agonist. Partial agonist will compete with full agonist for finitie number of receptor sites. Reduces potency of full agonist shifting ED 50 to the right