Lecture 3 - How do drugs work?

Question 1

What is the plasma membrane?

Answer 1

Selectively permeable membrane between the extracellular environment and cytosol

Question 2

How are drugs distributed throughout the body?

Answer 2

Blood and other bodily fluids

Question 3

What occurs on arrival at site of action?

Answer 3

Drugs act by binding to receptors usually located on outer membrane
Or by binding to receptors on enzymes within the cell

Question 4

Where are receptors?

Answer 4

Typically integral membrane proteins located at plasma membrane

Question 5

What is the role of receptors?

Answer 5

Recognise and bind to ligands creating a biological response

Question 6

How can receptor numbers be affected?

Answer 6

1. Upregulation (increased)
2. down regulation (decreased)

• Depends if conc. of agonist is low/high.

Question 7

What are ligands? & 2 types?

Answer 7

Ligands are chemicals which bind to receptors

• Agonists/antagonsits

Question 8

What are the 2 properties of Agonists?

Answer 8

1. Affinity - strength of binding to receptor
2. Efficacy (intrinsic activity) - ability to induce conformational change.

• agonists activate receptors and lets cell respond

Question 9

What are antagonists?

Answer 9

Ligands which block the receptor - have affinity but no efficacy.
- Prevent agonists from binding

Question 10

Cellular signalling? (Information)

Answer 10

• Cell signalling is part of any communications process that governs basic activities of a cell
• Aberrant cell signalling is responsible for diseases e.g cancer
• Many drugs are designed to target cellular signalling processes
• Improved knowledge of cellular signalling processes allows identification of novel targets for drug design and improved therapy.

Question 11

Describe signal transduction?

What does it enable?

Answer 11

• Intercellular signal chemical does not enter the cell
• Binding of the signal chemical to its receptor causes series of chemical changes within the cell, altering the physiology of the cell.

Enables amplification

Drugs can alter these effects in order to produce different call response

Question 12

What are the steps of signal transduction?

Answer 12

1. Direct opening of ion channels
2. Direct activation of an enzyme
3. Indirect opening/closing of ion channel
   Indirect activation/inactivation of ion channel

Question 13

Intracellular second messengers involved in transduction?

Answer 13

1. Cyclic nucleotides
2. Inositol Triphosphate (IP3) & diacylgIycerol (DAG)
3. Calcium ions (Ca2+)

Question 14

3 Examples of Receptor-Operated Ion Channels and their agonists?

Answer 14

Agonist Receptor Channel opened

acetylcholine nicotinic cholinergic catIon channels

Glutamate Excitatory amino acids Na2+ or Ca2+

GABA GABAa Cl- channels

Question 15

Enzyme linked receptors - what are the 3 domains?

Answer 15

1. Ligand binding domain
2. Transmembrane domain
3. Catalytic domain

Question 16

Tyrosine-Kinase receptors are a class of enyzyme-linked receptors. How do these work?

Answer 16

1. Agonist binds to receptor, activating it
2. Phosphate group is transferred onto specific amino acid (specific tyrosine)
3. This results in recruitment of proteins from the cytosol
4. Proteins become ‘scaffolded’ scaffold producing cell signal.

Question 17

What are the 3 components of G-protein coupled receptor signalling?

Answer 17

1: G-protein coupled receptors bind to specific agonist.
e. g adrenaline to adrenoreceptors / glucagon to glucagon receptors

2: the g-protein acts as a molecular switch
- Turns on when associated with gtp
- Turns off when associated with gdp

The effector itself converts gtp to gdp hence switching itself off. Specific receptors interact with specific g proteins.

3: Effector enzymes:
- Adenylyl cyclase: ATP ——> cAMP
-Phospholipase: PIP2 ——> DAG + IP3
cGMP phosphodiesterase: cGMP —–> GMP

All second messengers - change cell physiology

Question 18

Calcium signalling (Information)

Answer 18

Involved with: Muscle contraction, metabolism

• Effect of Ca2+ are concentration dependent
• Ca2+ is a second messenger BUT cannot be destroyed or created just moved between compartments.