measurements in pharmacology Flashcards
what is occupancy?
the proportion of receptors occupied
how is occupancy calculated?
occupancy = number of receptors occupied/total number of receptors
how can occupancy be measured?
via radioligand binding studies. specific binding = total bound - non specific binding
what is the law of mass action?
rate of a reversible chemical reaction is proportional to the product of the concentration of reactants
what is Kd? what is a high Kd indicative of?
Kd is dissociation constant. high Kd = low affinity
low Kd = high affinity
why might response measurement not give a direct indication of occupancy?
as we are not measuring ligand binding directly but the consequences of binding via activation of second messengers
when is a system said to have spare receptors?
if maximal response can be evoked when occupancy is low
what information does EC50 provide?
the potency; higher the potency, lower the EC50 value
what is a partial agonist?
when the response has a reduced Emax but the same EC50 value as other agonists
what is meant by affinity?
the probability of a drug molecule binding to a free drug receptor at any given instant
what is meant by intrinsic efficacy?
a measure of a single agonist-receptor complex’s ability to generate a response
what is the efficacy of a full agonist?
1
by what is the size of the response governed by?
total number of receptors and nature of receptor-response coupling
what is chemical antagonism?
where two substances combine in solution so the effect of the active drug is lost
what is pharmacokinetic antagonism?
can refer to a reduction in the drug that is absorbed, or a change in drug metabolism
what is physiological antagonism?
where two drugs interact with opposing actions and cancel eachother out
what is non-competitive antagonism?
blocks a step in the process between receptor activation and response
what is competitive antagonism?
antagonist acts at the level of the receptor and competes with the agonist for occupancy of the receptor
how is reversible competitive antagonism characterised?
shift of the concentration response to the right with no effect on the maximal response
what is dose ratio?
how many more times agonist is needed in the presence of an antagonist
how is dose ratio calculated?
concentration of agonist in the presence of an antagonist/concentration of agonist in the absence of antagonist
how can dose ratio be utilised to determine a numerical value for affinity of antagonist for receptor?
pA2 value is given by -log10 of the concentration of antagonist which produces a DR = 2
how can agonist potency be measured?
shild regression analysis. when log10(DR-1) = 0, pA2 is minus this value
what is irreversible antagonism?
when the antagonism cannot be reversed by washing the tissue with a drug-free solution
on what factors is pharmacokinetics dependent on? why?
1 - absorption 2- distribution 3- metabolism 4- excretion these factors determine the concentration and time course of drug distribution in the body
what are the routes of drug absorption?
oral sublingual rectal epithelial inhalation injection
what are the factors which affect drug absorption?
1 - site/method of administration
2 - molecular weight (affects rate of diffusion)
3 - lipid solubility
4 - pH and ionisation - only uncharged molecules can cross lipid bilayer
5- carrier mediated transport - active or facilitated
what are the major body compartments for drug distribution?
1- extracellular fluid - plasma 4.5% bw, interstitial fluid 16%, lymph 1-2%
2- intracellular fluids 30-40%
3- transcellular fluid 2.5%
4- fat 20%
what facilitates the blood-brain barrier?
tight junctions in the endothelial cells of blood cells
what is meant by drug metabolism?
the enzymatic modification of drugs before excretion
what happens in phase I and II of drug metabolism?
Phase I - chemical modifications in the form of oxidation, reduction or hydrolysis
Phase II - conjugation of functional groups
through which mechanisms are drugs excreted?
renal excretion- (glomerular filtration 20%, active tubular secretion, slow reabsorption)
GI excretion
lung excretion
describe the one compartment model
drug disappearance from plasma follows an exponential time course characterised by plasma half-life, which is proportional to volume of drug distribution, inversely proportional to rate of drug elimination
how is the one compartment model applied to repeated doses or sustained delivery?
plasma concentration approaches a steady state value within 3-5 plasma half lives. this depends on the frequency of drug administration
what is the method for a radioligand binding assay?
1- prepare cells or m membranes using detergent and centrifugation
2- add radiolabels to samples at different concentrations and equilibrate
4- when equilibrated, remove unbound drug by filtration
5- count the radioactivity of the filter
give an example of a drug that is an irreversible antagonist
the alkylating drug dibenamine on histamine responses in the guinea pig ileum
into which three parts is renal excretion of drugs separated into?
1- glomerular filtration (20% drugs removed this way)
2- active tubular secretion -pumped into filtrate and out into urine
3- slow reabsorption - things in glomerular filtrate reabsorped, drugs that are poorly lipid soluble are are excreted as they are slower to reabsorb
what does it mean when drug clearance is not fit by a single exponential?
the presence of the two compartment model where drug is distributed into a second compartment
