Agonists and Antagonists Flashcards
What are the 3 main molecular targets for drug action?
- Proteins
- Nucleic acids
- Miscellaneous targets e.g. metal ions and GIT contents
What is a receptor?
Protein target with which a naturally occurring chemical mediator binds specifically to initiate a cellular response
What are the two classes of chemical mediators?
- Cell surface receptors
2. Intracellular receptors
What is the function of cell surface receptors?
Act as a receptor for molecules too large or hydrophilic to cross the cell membrane
What is the function of intracellular receptors?
Act as receptors for molecules which are small enough and hydrophobic so can pass through cell membrane
What happens when a chemical mediator on binding with receptor?
Shape change which stabilises the active form of a receptor so enhances interaction with signal transduction mechanism
What are the 2 stages of drug action on receptors?
- Binding
2. Activation
What is the function of an agonist?
Mimic the action of the chemical mediator, cause a shape change so causes a response in a cell or tissue
What is the function of an antagonist?
Bind to the receptor but does not cause a shape change so there is no response in a cell or tissue
What 5 factors affect the size of a response to a receptor agonist?
- Concentration of drug molecule
- Affinity
- Intrinsic efficacy
- Natural of signal transduction mechanism
- Total numbers of receptors present
What 4 things can influence the concentration of a drug molecule?
- Dose given
- Route of administration
- Distribution
- Rate of elimination
What is the affinity of a drug?
Tendency of a drug to bind to a receptor (strength of attraction)
What is the intrinsic efficacy of a drug?
Ability of a drug to activate a shape change in receptor so cause response
What 2 factors affect the proportion of total receptors available occupied?
- [Agonist]
2. Affinity
How do most agonists bind?
Reversibly
What is the Occupancy Equation?
[Agonist] / [Agonist] + Ka
What does Ka stand for?
It is the drugs equilibrium constant
How is the Ka value of a drug found?
It is equal to the concentration of agonist when half the receptors are occupied
What does Ka measure?
Strength of bonds formed between agonists and receptors
What happens if a drug has a high affinity to a receptor?
Strong bonds form so small [agonist] sufficient to achieve high occupancy
Ka is a theoretical measure. What is the practical measure and how does it work?
EC50 which measures drug potency downstream of a receptor
What is a full agonist?
Drug which causes maximum response in receptors i.e. activates shape change in all receptors
What is a partial agonist?
Drug which produces a smaller than maximum response even at high concentrations
What is the efficacy of a full agonist?
1
What 4 types of coupling can affect the extent of amplification of the initial signal and size of a response?
- Chemical gating of ion channels
- Activation of G-proteins
- Direct activations of enzymes
- Regulation of gene transcription
What are antagonist drugs?
Any drug which reduces the response to another drug
What are 5 types of antagonist?
- Competitive
- Non-competitive
- Physiological
- Pharmacokinetic
- Chemical
What is a competative antagonist?
Drugs which compete with naturally occurring chemical mediators or agonists for a binding site on receptor without initiating a cellular response
What is the intrinsic efficacy of competative antagonists?
0
What is the competitive antagonist for B1 adrenoreceptor?
Atenolol
How does atenolol work?
Competes with agonist for binding site but cannot cause a shape change so the muscle does not contract
What is a clinical use of atenolol?
Prevent angina as ability of adrenaline and noradrenaline to increase cardiac work is blunted
What are the 2 classifications of competitive antagonists?
- Reversible
2. Non-reversible
What is the only way to influence reversible antagonists?
Increase concentration of agonists
What is the effect of a competitive reversible antagonist on the agonist log concentration response graph?
No reduction in maximum response but a greater concentration is needed to produce maximum response
Why do some antagonists bond irreversibly?
They form covalent bonds
What is the only way to overcome irreversible antagonists?
Create new receptors
What is an example of an irreversible antagonist drug?
Clopidogrel
What is the function of clopidogrel?
Anti-platelet drug to inhibit thrombus formation
What is the effect of a competitive irreversible antagonist on the agonist log concentration response graph?
Progressive reduction in maximum response to agonist without a shift in concentration
What is a non competitive antagonist?
An antagonist which affects action of agonist at some point in the chain leading to a response but does not compete for the same binding receptor as the agonist
Give 2 examples of how non competitive antagonists can work
- Binding to an allosteric site to cause conformational change on agonist receptor
- Interference with a component of the signal transduction pathway
What is a physiological antagonist?
An antagonist with an opposite affect to an agonist but achieves the result by acting on separate cells i.e. two systems are involved
What is an example of a physiological antagonist?
Parasympathetic nervous system releasing acetylcholine in nerves supplying heart to counter sympathetic response
What is a pharmacokinetic antagonist?
A drug concentration can be decreased if another drug interferes with its ADME
What are 2 examples of chemical antagonists?
- Heparin
2. Protamine sulphate
How are receptors initially divided?
Receptor families
How are receptor families divided?
Family members
What are receptor families based on?
Which mediators a receptor responds to
What 3 things are family members based on?
- Potency of endogenous mediators at receptors for that mediator in different tissues
- Selective stimulation by agonist drugs
- Selective blockade by competitive antagonist drugs
