Drugs And Receptors -- 8.1 & 8.2 Flashcards
Define ligand
A target which binds to a receptor and causes a response
Define affinity
The degree to which a receptor binds to a ligand
Define efficacy
The ability of a ligand to activate a receptor
Define agonist
Drugs that bind to a receptor and cause a response
– have affinity and efficacy
Define antagonists
Drugs that bind to a receptor but do not cause a response
- have only affinity and NO efficacy
- block the effects of agonists
What is binding determined by?
Affinity
What is activation governed by?
Efficacy
How many receptors does a cell have?
10,000 to 100,000 per cell
Hw can you get information regarding binding of drugs?
Use a radioligand (radioactive version of the ligand)
What is Bmax?
The maximum binding capacity
– gives information regarding the number of receptors
What is Kd?
The dissociation constant
– is a measure of affinity
– the concentration of a ligand required to occupy 50% of the available receptors
The lower the value, the higher the affinity
Define concentration
Th known concentration of drug at site of action
I.e. in cells or tissues
Define dose
The concentration of a drug at the site of action is unknown
E.g. Th dose that you give to a patient related to their weight
What law does binding obey?
Th law of mass action
– it is related to the concentrations of the products and the reactants (dynamic equilibrium)
Define potency
A combination of affinity and efficacy
- governed by the number of receptors
- a measure of the drug needed to produce a biological response
What are agonists?
Drugs that mimic endogenous ligands
Way are antagonists?
Drugs that block endogenous ligands
What is critical in determining drug action?
The concentration of drug molecules around the receptors
What determines the amount of receptors bound to receptors?
Concentration of the ligand
What effect will a drug which has good potency have on the EC50 and dose size?
Good potency = low EC50 = smaller dose needed
What effect will a drug which has bad potency have on the EC50 and dose size?
Bad potency = high EC50 = larger dose needed
What is functional antagonism?
Separate pathways mediate contraction and relaxation
E.g. Bronchi constriction and bronchodilation
How do side-effects of drugs come about?
Drugs can interact with adrenoceptors which are present in other areas of the body.
E.g. Asthma drugs target B-adrenoceptors which are also present in the heart, causing the heart rate to increase
Define spare receptors
Receptor numbers greater than needed to generate a maximum response
Why are spare receptors beneficial?
They increase the sensitivity so allow responses to be generated when there is a low concentration of an agonist
What can a cell do in order to change the agonist the degree of a response?
It can up-regulate or down-regulate in order to change the potency, affecting the maximal response
What stimulates changes in receptor numbers expressed on a cell?
Up-regulation is in response to low activity to increase sensitivity
Down-regulation is in response to high activity to decrease sensitivity
What are partial agonists?
Drugs which cannot produce a maximal effect even when they have a full receptor capacity
EC50 = Kd
Describe the potency of partial agonists in comparison to full agonists
Partial agonists can be more or less potent than full agonists
What is a particularly useful characteristic of partial agonists?
They can act as an antagonist against a full agonist
E.g. Buprenorphine antagonises morphine
Describe a clinical use of a partial agonist
Buprenorpnine acts as an antagonist against morphine so it is used to enable gradual withdrawal.
It also prevents the use of other illicit opioids
What kind of symptoms tend to occur in withdrawal syndromes?
The opposite effects of the acute drug effects
E.g. Pain –> lots of pain
Euphoria –> depression
What can facilitate the change of a partial agonist to a full agonist?
Increasing the receptor number
What indicates intrinsic activity?
A maximal response
What are the efficacy differences between partial and full agonists?
Partial agonists have a lower efficacy than full agonists
Describe reversible competitive antagonism
Commonest and most important in therapeutics
- antagonist competes with agonist for receptor sites
- relies on dynamic equilibrium between ligands and receptors
- inhibition is surmountable by addition of more agonist
What is the index of antagonist potency (IC50)?
The concentration of antagonist which give 50% inhibition
– it is determined by the strength of [agonist]
What occurs in the graph showing reversible competitive antagonists?
There is a parallel shift to the right
– curve shape stays the same just moves along and antagonist can be overcome
Give an example of a reversible competitive antagonists used clinically and why is it used?
Naloxone – high affinity, competitive antagonist and u-opioid receptors
Causes reversal of opioid mediated respiratory depression
– as it is high affinity, it outcompetes heroin for receptors
Describe irreversible competitive antagonists
The antagonist only dissociates slowly or not at all (due to covalent bond between ligand and receptor)
– over time/increased amount of antagonist, more receptors will be blocked
Is INSURMOUNTABLE
What happens to the curve when you increase the concentration of the antagonist?
The curve is shifted to the right as the concentration of the antagonist is increased. Eventually, the curve will decrease signifying the suppression of the maximal response as the antagonist blocks the receptors. It does not drop initially as the spare receptors are being filled.
Give an example of an irreversible competitive antagonist
Phenoxybenzamine – irreversible competitive alpha1-adrenoceptor blocker
- used to treat hypertension in pheochromocytoma
- blocks release of adrenaline which lowers rate of vasoconstriction
Describe non-competitive antagonism
Tends to bind to allosteric event (site other than the site where the natural ligand bind)
- provide novel drug target (may enhance selectivity)
- can act as an agonist or an antagonist
- do not compete for orthosteric site so are non-competitive
What effects are similar to non-competitive antagonists?
Similar to irreversible competitive antagonists
– can distinguish using specific tests
