L11 Mechanisms or Drug Action

Question 1

Define an agonist

Answer 1

a chemical that binds to and activates a receptor to produce a biological response

Question 2

Define an antagonist

Answer 2

Blocks the actions of an agonist.

A true (silent) antagonist does not produce any biological response on its own

Question 3

The all or nothing response is also called

Answer 3

the quantal response

Question 4

Partial vs full agonist

Answer 4

(Methadone = full, buprenorphine = partial)

Question 5

Competitive antagonist

Answer 5

Competes with agonist for the same receptor - atropine at Ach receptor

Question 6

Non-competitive antagonist

Answer 6

Binds irreversibly with receptor (omeprazole at histamine receptor) or interacts with different part of receptor to inactive it

Question 7

Receptors with some background energy are called

Answer 7

Constitutively active receptors: some background activity w/o agonist (histamine receptors and some GABA receptors)

Question 8

Two state model

Answer 8

• No ligand present = equilibrium lies far to the left (few receptors in activated state)
• Constitutively active receptors = some are in activated state
• Agonist have a higher affinity for R* conformation (absence of ligand)
• Inverse agonist has higher infinity for R than R* - equilibrium to the left
Neutral agonist: equal affinity for R and R*

Question 9

Receptors on Ion Channels

Answer 9

Type 1 receptors

Some drugs bind to sites on extracellular surface of ion channel (influence opening and closing) or interact with GPCR

Question 10

GABA-modulated Chloride Channel

Answer 10

• GABA (g-aminobutyric acid) = predominant inhibitory neurotransmitter in brain
• GABAA receptor gates Cl- Channel + GABA interacts
• Allows Cl- to enter cell
• Makes depolarisation difficult
Stabilise tissue and produce sedation

Question 11

G-Protein Coupled Receptors

Answer 11

• Type 2 receptors
• Gs activation increases AC activity and cAMP production
• GI activation reduces AC activity and cAMP production
• Gq activation increases PLC activity and IP3 + Ca2+ levels
• Signalling molecule + cell-surface receptor -> Gs or Gi -> Adenylate cyclase -> cAMP (2nd messenger)
Signalling molecule + cell-surface receptor -> Gq -> phospholipase C -> IP3, DAG (di-acyl glycerol) and Ca2+

Question 12

Physiological b2 receptor agonists - noradrenaline and adrenaline

Answer 12

• Noradrenaline + adrenaline bind G protein

Adenylyl cyclase -> cAMP -> Protein kinase 2 -> SM relaxation -> bronchodilate

Question 13

Salbutamol - synthetic β2 receptor agonists

Answer 13

Note that some people do not respond to β2 receptor agonists such as Salbutamol due to genetic differences in the molecular structure of their β2 receptors
Increase cAMP -> protein kinase A

Question 14

Enzyme-coupled receptors

Answer 14

Enzyme-linked Type 3 receptor -> protein phosphorylation cascade -> gene transcription -> protein synthesis + cellular effects

Question 15

Further detail

Answer 15

• Natural ligands include steroid hormones, e.g. testosterone
• Ligand binds to cytoplasmic receptor forming a “receptor-ligand” complex
• This allows binding to specific sites on DNA
○ (nuclear receptor-binding elements)
• Binding increases synthesis of mRNA (transcription)
Leads to protein synthesis via translation and an eventual physiological response due to these new proteins

Question 16

Receptors are not stable

Answer 16

• Receptors are dynamic - change (sometimes rapidly)
  
  • Receptor desensitization - short term effect & involves loss of intrinsic activity of receptor complexes
  • Receptor down-regulation: longer term effect & involves loss of receptor numbers