drug action Flashcards
what is a receptor and what does it do?
receptor in pharmacology is the term used for a class of macromolecules (mostly proteins) that are concerned specifically and directly with chemical signalling (signalling cascade)
are there limitless receptors and where are receptors found?
no, there is only a finite numbers and found in or on cells
How does high drug concentrations effect receptors?
they are saturable (as finite numbers of them so likely to get saturated)
what does it mean by receptors should display stereoselectivity ?
it means that the receptors should only recognise one of the naturally occuring isomers of a ligand (D or L)
what are the 4 receptor super families?
- ligand - gated ion- channel receptors
- G-protein-coupled receptors
- kinase-linked receptors
- nuclear receptors
what is a drug target & general examples?
term for class of cellular macromolecules that drugs bind to and mediate chemical signalling
examples - receptors, ion channels, enzymes & transport proteins
what is affinity?
the tendency of a ligand to bind to its receptor. selectivity of drug of one over another
what is an agonist?
A ligand that binds to a receptor and alters the receptor state resulting in a biological response. (cellular response - like opening up a door)
what is an antagonist?
A drug that reduces the action of another drug, generally an agonist. Many antagonists act at the same receptor macromolecule as the agonist. (like key that sits in key whole to prevent opening of door)
- they don’t do anything, just sit there preventing other agonist from binding
what is a partial agonist?
An agonist that cannot elicit as large an effect (even with 100% receptor occupancy) as can another agonist acting through the same receptors in the same tissue (ability to open door half way - less efficacy. example = beta blocker)
what is efficacy?
the tendency for an agonist to activate the receptor state resulting in a biological response
what is drug potency?
An expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect (e.g., EC50).
what is drug potency dependant on?
Dependent upon receptor (affinity, efficacy) and tissue (receptor numbers, drug accessibility) parameters
what is a dose and how do you decide what the dose is?
specified quantity of drug administered once or at stated intervals. Doses can be relative to body weight (e.g., mg/kg).
what value can we determine from the dose-response curve?
we can estimate EC50
(does required to get 50% of Emax)
when can you correctly apply dose-response curve?
only in vivo or human clinical scenarios (NOT in context of in vitro or cellular assay)
how does structure link to affinity?
structurally related drugs will have greater affinity than structurally dissimilair
what can lead to drugs binding to off targets and cause appearance of adverse drug reaction?
when higher dose (leading to higher blood plasma concentrations)
- this is also because no drug will be completely specific to particular receptor or in it’s physiological action
what is Hill-Langmuir model?
equation that models relationship between ligand concentration & receptor occupancy
what does logarithmic scale of Hill-Langmuir look like?
initially increases and the curve forms an elongated S shape
what is relationship between Ka and affinity of ligand for receptor?
lower Ka = greater affinity of ligand for receptor
what are competition experiments and what happens in them?
another experiment to estimate affinity
- competitively inhibit standard radio ligand , this gives us measure IC50 (tells you how much drug needed to inhibit biological process by half) and you can plug into equation which gives important value, Ki (inhibtion constant)
what is an example of a tricycline antidepressant and what are it’s targets & symptoms?
amitriptyline = has 2 targets - noradrenaline transporter & serotinin transporter
main mechanism = block reuptake of serotonin
symptoms = sedation, constipation & dry mouth
- symptoms caused by drug effect on off targets (higher dose = more likely to effect)
what is pKi and what is it’s relationship with affinity?
- log Ki
higher pKi = greater affinity
Roughly, how many receptors need to be occupied by agonists to give maximal response and why?
only a small % as 1 agonist molecule can set off signalling cascade that is progressively amplified within cell
so only small % of occupied receptors are required for tissue response
what is used to determine potency of agonists?
EC50 and Hill equation
what is drug potency?
an expression of activity of drug, in terms of concentration or amount needed to produce defined effect such as EC50 for agonists
what is EC50?
‘half maximal effective concentration’.
In a pharmacological context, this can be the concentration of a drug that is necessary to cause half of the maximum possible effect
what does drug potency depend on?
receptor - affinity & efficacy
tissue - receptor numbers, drug accessibility
what are partial agonists?
An agonist that in a given tissue, under specified conditions, cannot elicit as large an effect (even when applied at high concentration with 100% receptor occupancy) as can another agonist acting through the same receptors in the same tissue
what is reversible competitive antagonism?
- The most common and most important type of antagonist action.
- The antagonist ‘competes’ with the agonist for the same binding site on the receptor
- The interaction between the antagonist and the receptor is reversible.
How can you overcome reversible competitive antagonism?
you can add a bunch of agonists as this type of antagonism is surmountable - meaning if add enough agonists then overpowered
what effect does reversible competitive antagonist have on agonist concentration-response curve graph?
the curve is shifted to the right - without a change in maximal response or change in slope (i.e. shape remains same)
what is irreversible competitive antagonist?
- no matter how much agonist you put in, blockage remains
example = aspirin (on core drugs list)
what is non-competitive antagonist?
when acts on alternative active site on same enzyme - allosteric site
what are other ways of antagonism - not involving receptor?
- chemical antagonism (combining in chemical solution)
- physiological antagonism (2 drugs with opposite actions - cancel each other out)
- pharmacokinetic antagonism (reduces concentration of the active site in specific location)
what is chemical antagonism?
the antagonist combines in solution directly with the chemical being antagonised (e.g., chelating agents, used to treat lead poisoning, bind to heavy metals and form a less toxic chelate).
what is physiological antagonism?
Two agonists that produce opposing physiological actions and cancel each other out. Each drug acts through its own receptors (e.g., adrenaline relaxes bronchial smooth muscle reducing the bronchoconstriction of histamine)
what is pharmacokinetic antagonism?
= type of antagonism that’s about how body affects drug - like absoprtion, metabolism, excretion etc (affects of drug A & B could interfere with excretion of the other)
The ‘antagonist’ reduces the concentration of the active drug at its site of action (e.g., phenobarbitone increases hepatic metabolism of the anticoagulant drug warfarin)
- drug basically jumps up action in liver, lowers blood plasma conc. messes around with other drugs, good examples are alcohol and epilepsy drugs (drug list for next year but not this year)
- makes it less efficacious
what is example of non selective competitive antagonist?
propranolol
what is non-selective partial agonist example?
pindolol
