the effect of the drug on the body
the effect of the body on the drug
what are some types of drug targets?
receptors, enzymes, transporters, ion channels.
most drug targets are proteins
name some different types of receptor
ligand-gated ion channels,
G protein coupled receptors,
tyrosine kinase-linked receptors,
give an example of a ligand-gated ion channel
nicotinic ACh receptor
give some examples of G protein coupled receptors
muscarinic ACh, adrenergic, dopamine, serotonin and opiate receptors
what are some examples of tyrosine kinase linked receptors?
insulin, platelet-derived growth factor, epidermal growth factor
what type of receptors are steroid receptors?
what does the ADME acronym of pharmacokinetics stand for?
Absorption Distribution Metabolism Excretion
how does the nicACh receptor work?
ligand-gated ion channel. ACh binds to N-terminal of both alpha subunits - activates receptor. pore opens, and there's an influx of cations.
describe the structure of a G protein coupled receptor
single polypeptide chain, with 7 transmembrane-spanning alpha helices. ligand-binding domain is within membrane on 1+ of the alpha helices. 3rd intracellular loop is larger - interacts with G protein.
how do G protein coupled receptors work?
1. if an agonist binds to receptor, there's a conformational change - increased affinity for G protein.
2. G protein is activated by losing a GDP and gaining a GTP.
3. active G protein is then able to interact with other effectors like enzymes/ion channels.
what are the two main types of target for G proteins?
ion channels. secondary messengers.
how do DNA-linked (aka nuclear receptors) work?
located intracellularly. agonist binds to receptor. agonist-receptor complex transported to nucleus, by chaperone proteins. complex can bind to specific DNA sequences (through "zinc fingers"), altering expression of certain genes.
why is it useful to know what type of receptor is involved in a pathophysiological response?
can develop drugs that act at that receptor. can quantify drug action at the receptor.
define an agonist
a compound that binds to a receptor and activates it
define an antagonist
a compound that reduces the effect of an agonist - bind to receptors but don't activate them, do not induce a conformational change.
what is a drug's "EC50"?
the concentration of the drug to achieve half the maximal response - found at 50% on a dose-response curve. used to indicate POTENCY.
what are "full agonists"?
have high efficacy and are able to produce a maximal response while occupying only a small % of available receptors. will hit 100% on a dose-response curve.
what are "partial agonists"?
low efficacy. unable to elicit maximal response even if occupying all available receptors.
how would you identify a more potent (higher affinity) drug by comparing dose response curves?
will be more to the left - lower concentration of drug required to achieve the same response as the curve to the right
how would you identify a partial agonist on a dose response curve?
Emax is below 100% - the maximal response reached is less than 100%
describe the effects of a competitive antagonist
binds to receptors, preventing agonist from binding. parallel shift of dose-response curve to right. maximum response not reduced, just higher concentrations needed to reach it. amount the dose-response curve is shifted reflects affinity of antagonist.
what is affinity?
describes how well a ligand binds to the receptor - property shown by agonists and antagonists
what is efficacy?
describes how well a ligand activates the receptor - shown only by agonists
describe the concept of "receptor reserve"
there is an excess of receptors (spare receptors) - 50% response rarely corresponds to a 50% occupancy of receptors
describe "signal transduction"
agonist binds to receptor. there's a signalling cascade - several steps. this elicits a response.
describe "signal amplification"
at each stage in the signalling cascade induced by agonist binding to receptor, the signal is amplified - e.g. one enzyme is activated, and catalyses the next reaction more than once etc etc
what is drug tolerance?
reduction in drug effect (agonist) over time. occurs in response to continuous, repeated, high concentrations.
how does desensitisation of receptors occur?
they become uncoupled, or internalised, or degraded