Lecture 5 (Receptor Theory Antagonists) Flashcards
What are the 5 classes of Antagonist? (5)
(1) chemical antagonism
(2) pharmacokinetic antagonism
(3) physiological antagonism
(4) non-competitive antagonism
(5) competitive antagonism
How does chemical antagonism work?
Substances combine in solution so that the effects of the active drug is lost, i.e.the agonist is chemically altered by the antagonism
How does pharmacokinetic antagonism work?
Reduction in amount of drug absorbed, metabolised or excreted by another
What do drugs that affect pharmacokinetics also affect?
Concentration
Pharmacokinetics refers to processes which control concentrations of drugs in body, what are these? (3)
absorption, metabolism, excretion
How can you use pharmacokinetic antagonism to reduce drug concentration?
If we stimulate, we increase activity for enzymes responsible for breakdown of drugs, we therefore lower concentration of drugs
How can pharmacokinetic drugs affect drug concentration? (5)
Drugs that alter protein binding and filtration, alter urine flow or pH, or inhibit tubular secretion
What is physiological antagonism?
The interaction of two drugs with opposing actions in the body
e.g. noradrenaline raises arterial blood pressure by acting on the heart and peripheral blood vessels, while histamine lowers arterial pressure by causing vasodilation
What is non-competitive antagonism?
Blocks some step in the process between receptor activation and response i.e. it does not compete with the agonist for the receptor site and so is termed non-competitive
How does non-competitive antagonism work? (2)
Drugs that belong to this class stop agonist from having signalling function by competing indirectly by inhibiting function of a signalling molecule
Or could bind somewhere different on receptor to stop it form working
What is a competitive antagonist?
A competitive antagonist as a drug that bind to receptor to form complex, complex is not able to stimulate any downstream signalling
A competitive antagonist goes into same binding site of receptor as agonist, when it gets there it stabilises structure in such a way so that activity is not induced
What is competitive antagonism dictated by?
Dictated by the balance of the forward and reverse reaction at equilibrium
What are the two types of competitive antagonist? (2)
Reversible
Irreversible
How can we overcome effects of competitive antagonist?
Increased agonist concentration
What happens to response concentration curve when competitive antagonist concentration is increased?
Shifts right
(gradient and maximum stay same)
What happens to EC50 when increased concentration of antagonist is added?
Increases
How can we quantify shits of response concentration curves when adding competitive antagonists?
Use Dose ratio
How do we calculate Dose ratio?
Dose Ratio (DR) = conc of agonist in presence of antagonist/ conc of agonist in absence of antagonist
How do we calculate the affinity of competitive antagonist for receptor?
Perform schild analysis using dose ratio
What is dose ratio proportionate to in terms of Kd?
Dose Ratio (DR) = = Xb(conc of antagonist) / Kd (antagonist affinity constant) +1
What is on the axises for Schild’s analysis?
Y = Log value of (dose ratio) -1
X = Log value of concentration of antagonist
How do we find pA2 from Schild’s analysis?
Where this line crosses X axis we can get constant which is measure of affinity
Known as pA2 value
How do you calculate Kd from pA2?
Kd = 10^(-1 x pA2)
What dose dose ratio of 2 mean?
Dose ratio of 2 means you need twice as much of agonist to produce response in concentration of that antagonist
What is a partial agonist?
Like an agonist but can’t produce 100% max response
What does a partial agonist do in relation to a concentration (log) response curve?
Shifts right (like a competitive antagonist)
-Difference is that partial agonist can induce a signal
How can you counteract partial agonnist?
If you increase concentration of agonist enough, you can always achieve maximum response
How can competitive antagonists (reversible) be reversed?
Washing the tissue
Why are some competitive antagonists irreversable?
Irreversible as once it bonds to receptor, there is chemical reaction between protein and drug that form a bond, permanently connected, only way to get rid is to make completely new receptor
How can concentration response curve shit right without a change in maximum in the presence of irreversible competitive antagonists?
Spare receptors are present so can still achieve maximum response until they run out
What efficacy do competitive antagonists have?
Zero
What does the line on the plot of dose-ratio (compared to antagonist) for competitive antgaonist mean? And what shape is it?
It’s linear and the slope of the line is proportional to the affinity of the antagonist for its receptor
