Sites Of Drug Action Flashcards
Who was John Langley?
In 1905 Langley identified the idea of receptive substances by using an organ bath, adding different drugs and measuring a response.
He found that nicotine could be blocked by curare and similarly pilocarpine with atropine.
What did Paul Erhlich Coin? And when?
In 1908 Erhlich coined the term receptors. Won a nobel prize.
Compare an endogenous and exogenous agonist.
Endo comes from w in the body.
What are 6 sites of drug action?
Transporters, Receptors (Ligand-gated channels, GPCR, Catalytic, Nuclear), Enzymes
Compare an antiport and symport’s mechanism of action
Primary, uses ATP vs secondary, relies on electrochemical gradient
What are 4 key drug actions at transporters? IPTR
IPTR
- Inhib of CNS transporters can control neurotransmitter levels
- Involved in absorption, distribution and elimination (pharmacodynamics) of drugs
- can influence drug toxicity by controlling concentrations of drugs in a particular area
- development of resistance. seen with some anticancer, antiviral, antibacterial and anticonvulsant drugs as they actively pump them out of the target cell
What are ABC transporters?
ATP-binding cassette transporters use ATP hydrolysis to pump against a concentration gradient actively.
Name 2 important ABC transporters?
P-glycoprotein (p-gp) and Cystic fibrosis transmembrane regulator (cftr)
What are SLC transporters?
Solute-linked carrier
Secondary. Both solutes have higher concentrations on the same since of the cell. Pumps one out while pumping the other in at the same time.
Name 3 important SLC transporters and what drug commonly targets them?
Antidepressants.
Monoamine transporters; DAT (dopamine), NET (noraadrenaline), SERT (serotonin)
Compare the structure of Ligand-gated ion channels, G protein-coupled receptors, Catalytic receptors and Nuclear receptors.
L-G
- transmembrane domains: 4
- N terminus: outside cell
- C terminus: outside cell
- has intracellular area
- 4-5 monomers are required to be active.
GPCR
- transmembrane domains: 7
- N terminus: outside cell
- C terminus: inside cell
- G protein coupling domain inside cell
- 1 monomer are required to be active.
Catalytic
- transmembrane domains: 1
- N terminus: outside cell
- C terminus: inside cell
- 2 monomers are required to be active. (must be dimerised and autophosphorylated)
Nuclear
- transmembrane domains: 0
- N terminus
- C terminus: binding domain
- DNA domain: zinc fingers
Describe the mechanism of action of Ligand-gated ion channels and name 6 ligands that bind here.
the ligand binds, conformational change, ions flow in, change in membrane potential, cellular response.
Ach
ATP
Glycine
GABA
Glutamine
5-HT
What is the Nicotinic Acetylcholine (ACh) receptor?
A type of ligand-gated ion receptor. Has 5 subunits. 2 Ach molecules bind causing it to open and allow cation to pass through (Na+, K+, Ca2+ sometimes)
What % of the genome are G-protein-coupled receptors? How many have been matched (name some)?
3%
Muscarinic w/ Glucagon
Adenosine w/ Histamine
Canaboid w/ PTH
Dopamine w/ seratonin
How do catalytic receptors become functional?
Two monomers dimerize when a ligand is bound, and undergo autophosphorylation.
what are the 5 main types of catalytic receptors and provide some functions?
Receptor Tyrosine Kinases - e.g. insulin
Receptor Serine / Threonine Receptors
Cytokine Receptors - Associate w/ proteins that have tyrosine kinase activity
Receptor Guanylyl Cyclases - intrinsic cyclase activity e.g. ANP
Receptor Protein Tyrosine Phosphates - e.g. a tumour suppressor
What are EGFs and how do they trigger a signalling cascade?
- Epidermal Growth Factor receptor
- when activated during autophosphorylation leads to the recruitment of adaptor signalling molecules which relay signal.
What proteins are present in a nuclear receptors active and inactive forms?
Inactive
- co-repressor / inhibitory proteins
Active
- agonist binding causes a conformational change
- co-repressor dissacosiates
- co-activator recruited
- gene transcribed
Compare class 1 and class 2 nuclear receptors.
Draw Venn diagram comparing:
- hetero/ homo
- steroid/ lipid ligands
- high/ low affinity
- synthesised as inactive w HSP in the cytoplasm/ bound to co-repressors
- ligand binding induces HSP dissociation/ induces co-repressor dissociation, co-activator binds
What is the time scale for the 4 types of receptors? Why is this important?
Ligand-gates = milliseconds
G-protein = seconds
kinase-liked = hours
nuclear = hours
i.e. Asthma, would need something fast acting for bronchospasm
