26 - Antagonism Flashcards
Broad types of antagonists
1)
2)
3)
1) Competitive antagonist (competes for binding at receptor active site)
2) Non-competitive, at receptort (EG: allosteric enhancers or inhibitors)
3) Non-competitive, not at receptor (functional antagonism, pathway antagonism)
Factor that mostly determines potency of antagonist
Affinity
Determinant of immediate effect of antagonist
Pre-existing level of agonism present in system
Signal cascade from activation of beta-adrenoceptor by isoprenaline 1) 2) 3) 4) 5) 6) 7)
1) G protein (Gs) activated
2) Gs activates adenyl cyclase
3) Adynyl cyclase catalyses cAMP formation
4) cAMP activates protein kinase A
5) PKA opens L-type Ca2+ channel
6) Ca2+ influx into cell, Ca2+ release from sarcoplasmic reticulum
7) Increased contractility of cardiac muscle
Competitive antagonist of beta adrenoceptors
Propranolol
Pathway inhibitor of beta adrenoceptor in cardiac muscle
Verapamil.
Inhibits L-type calcium channel opening (allosteric inhibitor)
How do benzodiazepines work?
Allosteric enhancers of GABAa channels.
When GABA binds GABAa, Cl- enters neuron, hyperpolarises cell.
When benzodiazepine is bound to receptor, increases GABA affinity for receptor
Why is it hard to get specificity with competitive antagonism?
Because active sites of receptors are very conserved
Why is it easier to get specificity with allosteric drugs?
Because non-active site locations on receptors aren’t as conserved as active sites
Advantages of allosteric modulation
1)
2)
1) Specificity
2) Can have incomplete antagonism, so physiological modulation of site can continue
Surmountable antagonism
How difficult it is to overcome effect of antagonist
Indicator that an antagonist is surmountable
Max effect of function being antagonised doesn’t decrease.
Right shift on dose-response curve
Do competitive reversible antagonists have to be surmountable in vivo if they are surmountable in the lab?
Not necessarily
Is non-competitive antagonism mostly surmountable or not?
Mostly non-surmountable
Why is propranolol effect surmountable with isoprenaline but not exercise?
There is a limit to how much noradrenaline the sympathetic nervous system can deliver to the heart, not enough to overcome propranolol.
You can inject more isoprenaline.
