Pharmacodynamics II - The concept of antagonism Flashcards
What are the types of antagonists?
Chemical antagonist
Competitive receptor antagonist
Irreversible receptor antagonist
Negative allosteric modulator
Inverse agonist
Signalling pathway inhibitor
Functional antagonist
What are chemical antagonists?
Chemicals that bind directly to the soluble agonists (eg antibodies)
What does infliximab do?
It is a monoclonal antibody that binds to and inhibits pro-inflammatory mediator TNF-alpha which is a treatment used for rheumatoid arthritis.
What do competitive receptor antagonists do?
Compete with agonists for the same binding site on receptor
Competitive receptor antagonists have affinity for the receptor but no _____
Efficacy
What determines the effectiveness of the antagonist at inhibiting the agonist?
The relative concentration of both agonist and antagonist and the affinity of the antagonist to the receptor.
What are irreversible receptor antagonists?
Antagonists that form an irreversible bond with agonist binding site preventing agonist from binding to receptor.
What is an example of an irreversible receptor antagonist?
Phenoxybenzamine is converted to aziridinium ion which forms a covalent bond with agonist binding site at the alpha-adrenoceptor
What happens to reaction when an irreversible receptor antagonist is added?
The number of effective receptors decreases so the amount of agonist to carry out any effect is increased and the overall effect is diminished.
Why is phenoxybenzamine rarely used?
It has many other target receptors (it lacks selectivity for alpha adrenoceptors)
Which drug is used commonly that is a slowly reversible antagonist?
Tiotropium
What conditions is tiotropium used for?
COPD/Asthma
Why is tiotropium chosen over other drugs?
It has a long duration of action which means it can be used daily and will improve patient adherence
What are allosteric antagonists?
Antagonists that bind to distinct site from binding site which induces conformational change in the receptor and thus reduces the affinity and efficacy of the agonist.
What is another name of allosteric antagonists?
Negative allosteric modulators (NAMs)
Are allosteric modulator effects reversible?
Yes
Can NAM antagonism be overcome with higher concentration of agonists?
Yes
What is the ceiling effect in NAM?
Binding sites for allosteric modulators are limited and so there is a ceiling effect for their action.
What is the biggest advantage of using NAM?
The ceiling effect is associated with fewer side-effects and less likely to cause excessive blockade compared to other antagonists.
What is maraviroc?
A drug designed to reduce HIV-1 rate of reproduction.
Maraviroc is a NAM that bids to CCR5 receptor decreasing viral entry into target host cells.
What are inverse agonists?
Agonists that bind to receptors that are active in their unbound state
When are inhibitors of intracellular signalling used most effectively?
When cells express unique signalling molecules that aren’t used by many other cells.
What does imatinib do?
It inhibits expression of BCR-Abl by leukemic cells which is a singnalling molecule that is essential for their survival.
What are functional antagonists?
Agonists that act on receptors that produce the opposite effects within the cell than what the problematic receptor is causing.
Example of functional antagonists?
Epipens containing adrenaline to oppose the effect of histamine
What kind of effect do functional antagonists cause?
Dose-dependent but limited antagonism due to ability for both receptor agonists to be saturated
