Lecture 3 - How do drugs work? Flashcards
What is the plasma membrane?
Selectively permeable membrane between the extracellular environment and cytosol
How are drugs distributed throughout the body?
Blood and other bodily fluids
What occurs on arrival at site of action?
Drugs act by binding to receptors usually located on outer membrane
Or by binding to receptors on enzymes within the cell
Where are receptors?
Typically integral membrane proteins located at plasma membrane
What is the role of receptors?
Recognise and bind to ligands creating a biological response
How can receptor numbers be affected?
- Upregulation (increased)
- down regulation (decreased)
- Depends if conc. of agonist is low/high.
What are ligands? & 2 types?
Ligands are chemicals which bind to receptors
- Agonists/antagonsits
What are the 2 properties of Agonists?
- Affinity - strength of binding to receptor
- Efficacy (intrinsic activity) - ability to induce conformational change.
- agonists activate receptors and lets cell respond
What are antagonists?
Ligands which block the receptor - have affinity but no efficacy.
- Prevent agonists from binding
Cellular signalling? (Information)
- 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.
Describe signal transduction?
What does it enable?
- 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
What are the steps of signal transduction?
- Direct opening of ion channels
- Direct activation of an enzyme
- Indirect opening/closing of ion channel
Indirect activation/inactivation of ion channel
Intracellular second messengers involved in transduction?
- Cyclic nucleotides
- Inositol Triphosphate (IP3) & diacylgIycerol (DAG)
- Calcium ions (Ca2+)
3 Examples of Receptor-Operated Ion Channels and their agonists?
Agonist Receptor Channel opened
acetylcholine nicotinic cholinergic catIon channels
Glutamate Excitatory amino acids Na2+ or Ca2+
GABA GABAa Cl- channels
Enzyme linked receptors - what are the 3 domains?
- Ligand binding domain
- Transmembrane domain
- Catalytic domain
Tyrosine-Kinase receptors are a class of enyzyme-linked receptors. How do these work?
- Agonist binds to receptor, activating it
- Phosphate group is transferred onto specific amino acid (specific tyrosine)
- This results in recruitment of proteins from the cytosol
- Proteins become ‘scaffolded’ scaffold producing cell signal.
What are the 3 components of G-protein coupled receptor signalling?
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
Calcium signalling (Information)
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.
