Receptor theory and Classification of drug action Flashcards
What kinds of regularly proteins are involved as primary drug targets? (4)
- receptors
- enzymes
- carrier molecules
- ion channels
What is a receptor?
A target molecule through which soluble physiological mediators produce their effects.
What happens when a ligand binds to a receptor?
Leads to a ligand-receptor complex which leads to a response.
What are the fastest receptor effects?
G protein-coupled receptors
seconds
A minimum —– point attachment of a drug to a receptor site is required.
3 point attachment
What type of bonds are irreversible?
Covalent bonds - this type of bond formation is rare except in a rather toxic situation.
2 principles of binding studies:
- understand affinity of selected ligands for the receptor of interest
- analyse the mechanism. of interaction of ligands with the receptor alone, and in combination
3 types of binding studies:
kinetic experiments
saturation experiments
competition/modulation experiments
What is radio receptor assay?
Measures the binding of drugs to receptor using a tissue preparation
What would be the curve produced from the radio receptor assay?
- total binding
- non specific binding
allows us to calculate specific binding.
Define Agonist
A substance that interacts with a receptor leading to an observer biological response.
Agonist can be endogenous or exogenous, what does this mean?
Endogenous - found naturally in the body
Exogenous - administered into the body
Dose-response curve would show…
Threshold response - minimum concentration required to produce a response
Ed50 = concentration of the drug that would produce 50%maximum response.
Ceiling - maximum response.
What is a partial agonist?
Binds like an agonist but cannot produce the same maximal biological effect, regardless of the dose.
What is an inverse agonist?
Binds like an agonist but has a negative effect - like an antagonist.
What is a biased agonist?
Not natural substances used in drug development to produce ligands which will produce a favourable cellular response over e.g. side effects.
Define spare receptors
receptors which exist in excess to those required to produce a full effect.
Define Intrinsic activity
Ability of the agonist to activate the receptor as compared to the maximally active compound - like efficacy.
Define antagonist
An antagonist inhibits the effect of an agonist by binding to the same receptor and not producing any effect. Simply blocks.
What types of antagonists are there? (4)
Competitive
Non competitive
Allosteric
Physiologic
What is the difference between the competitive vs the non competitive antagonists?
Competitive binds to the same site as agonist but is reversible
Noncompetitive is not reversible
Define allosteric antagonists:
Antagonists and agonists bind to different sites on the same receptors.
Define physiological antagonists:
Two drugs have opposite effects through differing mechanisms. Contradicting.
How to overcome competitive antagonists?
Increase the dose of agonist
Can we overcome non-competitive antagonists?
No, hence the name.
What happens to the dose response curve of an agonist in the presence of a competitive antagonist?
The curve shifts to the right meaning a higher concentration of agonist is needed to produce the response.
What happens to the dose response curve of an agonist in the presence of a non competitive antagonist?
The curve shifts to the right but cannot be overcome by increasing the concentration of agonist.
What are the types of allosteric antagonists? How would they look on a curve?
Competitive and Non-competitive.
Same as the other antagonists.
Define Heteroreceptors
A receptor that regulates the synthesis and/or the release of chemical mediators other than its own ligand.
Define Auto-receptor
A macromolecule typically found in the nerve ending that regulates the synthesis and/or the release of its own ligand.
Receptor down-regulation is..
a phenomenon whereby an agonist actually induces a decrease in the number of those receptors available for binding.
Receptor up- regulation is…
a phenomenon whereby an agonist actually induces an increase in the number of those receptors available for binding.
Define affinity
the ability of a drug to combine with its receptor.
A ligind of low affinity requires..
a higher concentration to produce the same effect.
A ligand of high affinity requires..
a lower concentration to produce the same effect.
Efficacy is a measure of the…
biochemical or physiological effect which results, following the binding of a drug to its target.
Efficacy is a measure of the maximum effect the drug can produce.
Potency refers to..
The dose of a drug required to produce a specific effect of given magnitude.
Potency is dependent upon…
Affinity and Efficacy.
More potent means…
An effect is achieved at a lower concentration.
2 fathers of receptor theory:
John Langley
Paul Ehrlich
What did John Langley do?
Theory
Suggested that there must be a receptive substance causing a response - lead to the drug action.
What did Paul Ehrlich do?
Theory
Side chain theory of cellular interaction
Immune cells have receptors which allow toxins to bind - the cell would be activated and more receptors produced - released into the bloodstream as antibodies to neutralise the toxin.
Occupation Theory
Drug effect is directly proportional to…
Drugs act on independent binding sits and activate them - resulting in a biological response.
The response increases when there are more complexes.
Drug effect is directly proportional to the number of receptors occupied (not necessarily true)
What did Emil Fischer say?
Theory
Lock and Key analogy
lock - enzyme
key - substrate
has to fit like a lock and key.
Explain Rate Theory
Pharmacological activity is directly proportional to the rate of dissociation and association, not the number of receptors occupied.
Describe Agonist Partial Agonist Antagonist in terms of rate theory:
Agonist - fast association and dissociation
Partial Agonist - drug with intermediate association and dissociation.
Antagonist- fast association and slow dissociation.
Explain Induced-Fit theory
Contradicts lock and key.
The receptor alters the conformation of its binding site to produce drug-receptor complex.
Explain Macromolecular perturbation theory:
When a drug-receptor interaction occurs one of two types is possible:
- a specific conformational perturbation leads to a response (agonist)
- a non specific leads to no response (antagonist)
Explain Activation-Aggregation theory:
A drug receptor (in absence of drug) still exists in an equilibrium between an activated state (bioactive) and an inactivated (bio-inactive)
agonist binds to activated sate
antagonist binds to inactivated state
What is the current theory?
The two state receptor model
A receptor always exists between the R state (resting) and R* (activated state) which are in equilibrium with each other.
Normally when there is no ligand, where is the equilibrium?
in the R - resting state.
What is a drug?
All chemicals other than food that affect living processes.
Can either be a medicine or a poison.
How are drugs classified? (3)
- chemotherapeutic agents - used to cure infectious diseases and cancer
- pharmacodynamic agents - used in non-infectious diseases.
Miscellaneous agents - e.g. anesthetics.
Where can drugs interact?
Molecular, cellular level
on tissues
on whole systems e.g. CNS
Describe Physical mechanisms
No chemical reaction or change in cells - just physical effect
Describe Chemical mechanisms
Drugs act by producing chemical reactions in the body.
Describe Drug-Receptor Interaction
Drugs act on the cell membrane by physical/chemical interactions - this is through drug receptor sites on membrane.
Define Ligands
Substances, molecules or compounds which bind with receptors present in the body.
Common points between Ligands and Agonists:
Coupling of the receptor - the receptor is occupied and causes an effect.
Drug binding may be of 2 types…
Reversible binding
Irreversible binding
What is Desensitization of a receptor?
When the maximum response is achieved - the response starts to decrease although agonist still binds.
No one knows the mechanism for this.
Explain Drug-enzyme interaction
Similar to drug-receptor interactions, but with enzymes.
Activation/inhibition of enzymes.
Combination of drugs with enzyme can be competitive or non-competitive.
Explain Drug-channel interactions
Drug acts on channels which interferes with the flow of ions e.g. Na+, Cl- channels.
Explain Miscellaneous mechanisms
Drugs do not act through any of the mechanisms already mentioned.
Explain Non-specific interactions
Drugs that act physically outside of cells - e.g. neutralisation of stomach acid by antacids.
Actions of drugs are..
the biochemical physiological mechanism by which the chemical produces a response in living organisms.
The effect is…
the observable consequence of drug action.
Interactions of drugs can lead to.. (4)
Additive effect - total effect is sum of effect by both drugs
Antagonist effect
Synergistic - net effect is bigger than the sum of the effects produced.
Cumulative - long term use, and additive effect.
Types of effects by drugs: (4)
primary effect - desired
secondary - side effects that could be harmful
local effect - only on application
systemic - away from the site of administration e.g. oral.
Examples of mode of drug action (2)
- killing or weakening foreign organisms - selective toxicity.
- stimulation and depression - drugs act by stimulating or depressing normal physiological functions.
