L.1,4 Mechanism of drug action/drug targets Flashcards
What is affinity vs potency
Affinity: attraction of a ligand for a receptor - how easily they bind together
Potency: the ratio of response compared to the concentration (or dose) of agonist. - how little does it take to get a big response?
What are the 6 potential drug targets
Ion channels, Enzymes, Carrier molecules and Receptors, Cytokines and DNA
What are the 4 types of receptors, basic mechanism and their time scales of working
- Ligand gated ion channels: miliseconds
specific ligands open channel that is selective for one ion through multiunit structure, by changing conformation of the “gate” allowing fast opening. - G protein coupled receptors: seconds
Ligand activates receptor which activates G protein which can go onto open ion channels or activate enzymes - Tyrosine Kinase/cytokine linked receptors: hours/days: Ligand activates receptor/enzyme complex which starts phosphorylation leading to alteration of gene transcription
- Intracellular nuclear/Steroid receptors: Hours : Ligand is lipid soluble, crosses the membrane to find receptor in the cytosol. Activated receptor goes to nucleus to alter gene transcription.
Give examples of ionotropic receptor agonists good and bad
- excitatory: ACh/glutamate agonists: increase Na+ and K+ permeability which increases depolarisation-> AP
- inhibitory: GABAa agonists : increase opening frequency or duration of Cl- channels hyperpolarising cell
how does a tyrosine kinase receptor work
Involved with mediating the actions of GF, cytokines and certain hormones, receptor funtions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins . Eg, VEGFR2 protein
When do receptors undergo conformation change which leads to activation/ inhibition of cell signalling
Upon binding a neurotransmitter/hormone
How do drugs bind to receptors
4 different bonds in order of strength
Van der waals, hydrogen binding, ionic interactions, covalent (basically permanent).
How is Affinity measured
Fractional occupancy: measures fraction of receptors that have a ligand bound to a receptor when we add a particular concentration of ligand.
When there is a higher fraction of binding for a lower concentration of ligand (drug), the affinity is higher.
What is the relationship between affinity and actual biological response
The relationship between binding and response are not directly proportional. There is some amplification where low numbers of receptor occupancy can cause max response. Some factors downstream from receptor binding may interact to produce the final response.
What is EC50 (C for concentration - ED50 for dose)
On a graph of concentration of drug vs % effect
EC50 is the concentration of agonist where 50% of maximal response is produced. Used as measure of potency- where the lower the EC50, the more potent it is.
What is the difference between dose and concentration
Dose is the actual amount of medicine put in the body, whereas the concentration is the amount measured in the blood after pharmacokinetics has happened.
Later this concentration goes on to have an effect through pharmacodynamics
What is efficacy and what is it measured by on a graph of concentration of drug vs % effect.
Efficacy: The ability of the drug to bind to receptor and cause a change in the receptors action.
Measured by Emax, conc when % effect is 100.
What are agonists, inverse agonists, antagonists and their the affinity and efficacy characteristics.
Full Agonist: positive efficacy: raises activity level to max above basal rate. Increased affinity.
Partial agonist raises activity level below max above basal rate.
Inverse agonist: negative efficacy- decreases activity rate below basal
Antagonist: affinity but no efficacy- adds no addition to basal rate activity so can’t be stimulated to become higher.
What are the two types of Antagonist.
Reversible competitive: on/off binding to compete directly with agonist and therefore decrease response achievable by agonist: antagonist - but can be overcome with increased conc of agonist so max response can still be achieved. Most commonly used.
Irreversible competitive: covalent bonding reduces available sites for agonist reducing the max response achievable
What is selectivity and the relevance to drug therapy
Selectivity is how drugs can preferentially bind to a certain subtype of receptor more than others.
It is important because although one compound can match with different subtype receptors from the same family, having a preferential binding for one subtype leads to a greater effect for that subtype. Subtypes affect different places and functions so you may not want to trigger the other subtypes for unwanted side effects.
