4. Antagonists Flashcards
Steps of antagonist to effect
- receptor
- antagonist-receptor complex
- effect
Explain steps of propranolol to effect
- on beta-adrenoreceptor
- propranolol-beta-adrenoreceptor complex
- decreased blood pressure
3 classes of antagonist
- chemical
- physiological
- pharmacological
Explain ‘chemical antagonists’
- binding of two agents to render active drug inactive
- commonly called chelating agents
- example is protamine binds/sequesters heparin
Explain physiological antagonists
- two agents with opposite effects cancelling each other out
- e.g glucocorticoids and insulin
Explain pharmacological antagonists
- binds to receptor
- blocks normal action of agonist on receptor responses
Antagonists can be receptor or non-receptor. 2 types of non-receptor antagonists are …
- chemical
- physiological
Explain how non-receptor antagonists work
- doesn’t bind to same receptor as agonist but inhibits ability of agonist to initiate response
- this occurs by inhibiting agonist directly by inhibiting a downstream molecule in activation pathway or activating pathway that opposes agonist
- chemical ones inactivate agonist before it’s opportunity to act e.g chem neutralisation
- physiological ones cause physiological effect opposite to that induced by agonist
Receptor antagonists can have … binding or … binding and both of these can be … or …
- allosteric
- active site
- reversible or irreversible
A reversible active site binding antagonist is …
What happens here?
- competitive
- action of agonist will come back when antagonist is lost
- adding more agonist gives it more chance of binding and vice versa
Reversible and irreversible allosteric binding antagonists are non-comp/comp?
non-comp
(all are non-comp except reversible active site binding)
Pure antagonists alone have what effect when binding to receptor?
no action
What kind of efficacy do antagonists have?
none
AR* for antagonists doesn’t exist
How do competitive active site antagonists work?
- binds and prevents agonist action but can be overcome with increased agonist conc
- causes parallel shift to right of agonist-response curve
How do non-competitive active site antagonists work?
- binds and form irreversible covalent bonds with receptor
- causes parallel shift right of agonist-response curve AND reduced maximal asymptote
How do non-competitive allosteric antagonists work?
- signal transduction rather than receptor effects
- downstream responses are blocked e.g calcium ion influx
- reduces slope and maximum of dose response curve
How does an agonist curve look with a competitive antagonist?
Why?
- same form but displaced to the right
- same maximal response
- linear portion of curves are parallel
- because comp antagonist binds reversibly with receptor, gives rise to antagonism which can be overcome by increased conc of agonist
Equation for dose ratio
agonist +antagonist EC50 (x)/agonist EC50 (y)
What is the Schild equation?
r-1 = [B]/Kb
r is dose ratio
B is antagonist conc
Kb - antagonist dissocation constant
What do pA2 values describe?
When does it work?
the activity of a receptor antagonist in simple numbers
pA2 = -logKb
- only works if relationship is linear and slope of Schild plot is 1/a comp antagonist
Implications of comp antagonists on clinic
- extent of agonist inhibition depends on conc of competing antagonist (varies in response to normal physical activity as well as disease states)
- extent of inhibition depends on antagonist’s conc (inter individual diffs in metabolism or clearance influence plasma concs)
How does the agonist curve look with an irreversible antagonist?
Why?
- don’t have same form and reduced maximal response
- ant binds irreversibly to receptor and gives rise to antagonism which cannot be overcome by increased conc of agonist
Irreversible antagonism on a concentration response graph
- increased EC50
- duration of effect related to receptor turnover
- receptor reserves allow parallel shift to right
Weak partial agonists are also …
irreversible antagonists
Which is most common? Competitive or irreversible antagonism?
competitive
Examples of competitive antagonists
- cimetidine at H2 receptor
- tamoxifen at oestrogen receptor
Examples of irreversible antagonists
phenoxybenzamine at alpha1 adrenoreceptor
Why are reversible inhibitors advantageous?
- once inhibited, receptor has to be regenerated
- extreme situations can be avoided
- receptor exists for a reason in the first place and don’t want to remove function completely
How does a non-comp antagonist work?
- blocks signal transduction events
- inhibit agonist action by stopping something that signals outside
- no physical blockage
- reduces slope and maximal effect
- e.g nifedipine blocks calcium ion influc
Define ‘therapeutic window/index’
proportion of unwanted effects of all effects like sickness or headache
Equation for risk:benefit ratio
TD50/ED50
or
LD50/ED50
What does it mean to have a small or large therapeutic window?
- large means concentration we need to give desired effect is much lower than conc where we see unwanted effects
- small means the gap is smaller and it’s easier to get side effects
Example of drug with small or large TI
small is warfarin
large is penicillin
