Midterm I: Drug Targets - Blood Pressure Regulation Flashcards
agonist
substance or drug that binds to a receptor and generates an effect
antagonist
substance that generates no biological effect on its own but influences receptor response to an agonist
prodrug
a substance that is converted to the active form of the drug via liver metabolism
Gi signaling cascade
- inhibit activity of adenylate cyclase, leading to decreased cAMP production, inactivating cAMP dependent protein kinases and substrates are not phosphorylated
- responses are generally quick and mediate moment to moment control of many physiol functions
pharmacokinetics
subfield focused on the specific details of drugs and the molecular-level receptor interactions
ligand gated ion channel
- open or close in response to binding of small signaling molecules (various AAs, NTs)
- play important role in CNS synapses as common drugs for psychiatric conditions target them
voltage gated ion channel
- transmembrane receptors
- rapidly respond to changes in membrane velocity
- movements of charged AAs the TM electric field change position in response to to changes in voltage, allowing the protein to open or close rapidly
EC50
in the context of a conc-response curve, refers to the conc of a drug that yields 50% of its maximal biological effect
potency
refers to concentration dependence (the smaller the EC50 of a drug, the less of it is needed to produce a given response, and the more potent it is)
Emax
the maximal biological effect observed from a drug
efficacy
term referring to the maximal effect o fa drug (the higher the Emax of a drug, the greater efficacy it’s said to have)
full agonist
generates the maximal observed effect (elicits full biological response)
partial agonist
generates a fractional effective (its maximal response is less that the possible biological Emax)
inverse agonist
inhibits receptor baseline activity, leading to an overall decrease in activity
tyrosine kinase receptors, TKRs
- transmembrane
- ligand binding triggers dimerization, they auto-phosphorylate (usually at crit Tyr residues) and become activated, able to phosphorylate internal systems
- drugs that inhib or stim their activation will influence downstream signaling mechanisms
- common in immune systems
drug effect equation
Emax x [drug]
E = ———————-
[drug] + EC50
or
Emax
E = ———————-
1 + (EC50/[drug])
orthosteric binding site
the active site that binds and agonist
competitive antagonists
suromountable
- do not affect Emax (with a high enough conc of agonist, you can eventually elicit the response) but do shift the EC50 right (as you need a higher conc of the agonist than usual to generate the response)
- compete for the same orthosteric binding site as the agonist
(reduce potency but not efficacy)
non-competitive antagontists
non-surmountabe
do not generally affect EC50, but do drop Emax (no matter how much agonist you add, you never reach the maximal response)
-bind to an alternate, allosteric site, and can therefore not be out-competed by the agonist
(reduce agonist efficacy but not necessarily potency)
-binding can prevent activation of the agonist bound receptor, but might also lead to a change in the shape of the binding site which could reduce agonist potency
irreversible competitive antagonism
-reduce efficacy by binding irreversibly to the orthosteric site (usually bind forming a covalent or chemical bond)
allosteric potentiation
-drugs that bind an allosteric site and thereby enhance the receptor response to an agonist (increase efficacy, potency, or both)
one example of positive allosteric modulators are benzos, which increase the activity of GABA signaling at its A receptors to compensate for the receptors lost during tolerance
allosteric binding site
binding to a receptor site other than the orthosteric (active, agonist binding) site
receptor reserve
as you take more and more receptors out of the system, it can compensate to an extent by enhancing the response of those remaining to generate the full biological response (there is a reserve of receptors that aren’t all needed to elicit the maximal response)
-eventually though, too many are taken out to compensate, leading to a drop off in efficacy
considerations of oral dosing
- first pass metabolism (will enough of the drug in its current form make it where it needs to? what are the metabolites and their effects)
- solubility (can it be absorbed into the gut cells?)