Receptor theory Flashcards
What is the usual way drugs elicit a physiological response?
Through binding to receptors
Give an example of a drug which ellicits a response without binding to a receptor
Antiacids - mediated by their chemical properties, are alkaline and neutralize gastric acid in the stomach
What are drugs?
Chemical compound administered to produce a desirable physiological or psychological affect (where side effects are undesirable)
What is a receptor?
A molecule to which a drug can bind
How do drugs bind to receptors?
Weakly: through van der Waals forces, H bonds and ionic interactions Reversibly
What are the four main types of receptor?
Ion channels (neurotransmitter receptors) G protein coupled receptors (Intracellular cascade response) Enzymatic (transmembrane, binding initiates catalytic cascades) Intracellular (e.g steroids are lipophilic and can enter the cell and act on an intracellular receptor)
Give an example of a drug affecting an ion channel receptor
Adenosine is a neurotransmitter which makes us feel sleepy, caffeine blocks its activity
Give an example of a drug targetting a G coupled receptor
Epinephrine binds to G coupled receptor to initiate AC -> cAMP pathway and stimulate muscle contraction, used to treate acute anaphylaxis (allergy)
Give an example of a drug affecting an enzyme coupled receptor
Insulin used to treat diabetes! Binds to insulin tyrosine kinase receptor, resulting in GLUT4 translocation
What are the two vital properties of a receptor?
- Recognition, must recognise drug with conformation allowing saturability, reversibility, stereoselectivity, specificity and tissue specificity 2. Transduction, different receptor types linked to effector systems wither directly or through signal amplification systems
What questions must be asked to predict a drugs affect in a particular tissue
- Can the drug get to the tissue (e.g can it cross the blood brain barrier)?
- Can we get enough og the drug to the receptor in order to ellicit equilibrium?
- How will the downstream signalling apparatus affect the response?
What is the difference between an agonist and an antagonist?
Agonist - elicits cellular response Antagonist - prevents actions of agonist
What are the properties of an agonist?
- An affinity for the receptor with a high strength of attraction - Efficacy (ability to elicit physiological response)
What is rational drug design?
Find naturally occurring molecules which bind to a receptor and create synthetic analogues (as proteins administered as a pill would be broken down in the stomach)
What is a typical dose response curve?
- Biological response graded with does up to limits of the physiological system - As we administer more drug more receptors are occupied and so increasing the effect
What is the law of mass action?
[A] + [B] <=> [AB] where k1 = rate on and k2 = rate off
What is the a) dissociation and b) association constant?
a) ‘Kd’ Rate at which drug receptor complexes dissasemble (k1/k2 or [D][R]/[DR])
b) ‘Ka’ Rate at which drugs assemble ( 1/kd or k2/1 or [DR]/[D][R])
What is occupancy theory?
That the effect of a drug corresponds to the number of receptors occupied
Response = [DR]/[RT]
Where DR is the number of occupied receptors and RT is the receptor total
(HOWEVER NOT ALL RECEPTORS NEED TO BE OCCUPIED FOR MAXIMUM EFFECT - DETERMINED BY BIOLOGICAL SYSTEM)
What are the limitations of receptor theory?
- Can’t assume that all ligands and receptors are equally available to eachother - Assumption that binding is reversible - Assumption that binding does not alter drug or receptor - Assumption of no intermediate binding
What are the advantages of logging drug dose/concentration for a dose response curve? What shape does it take otherwise?
Normally - rectangular hyperbola
Log - sigmoid cruve
- Portion between 10% and 90% response is linear making it easier to calculate points
- Gives us 4 parameters to measure: base line, slope, EC50 and maximal response
What is EC50?
Effective agonist concentration required to give 50% effect (work out max and min response and divide by two, reverse log of dose)
What is a full agonist?
Drug that can achieve maximal physiological response
What is the effect of a more potent drug on a dose response curve for a full agonist ?
Moves curve to the left - less drug needed to elicit maximum response
What is the result of positive and negative cooperativity on the dose-response curve?
Positive - steepens slope Negative - flattens slope as it is harder for drug to work
What are the 3 important elements of a does response curve?
- Baseline response - Slope (rate of change with receptors being occupied) - Maximal response possible by biological system
What is the effect of a partial agonist on a dose response curve?
Maximal response is lower as will never fully activate the biological system
What is cooperativity?
Where binding is altered if there are other ligands present on the same receptor (co-agonists)
What are competitive antagonists?
Bind reversibly with receptor to form complex with no response, can still be overcome by agonist (dose response curve moves to the right)
What are non-competitive antagonists?
Bind irreversibly (max response cannot be achieved)
What are the 3 methods by which a drug response is ended?
- Desensitisation 2. Receptors are internalised 3. Downregulation of receptors
Define efficacy
The ability of a drug to initiate a response, antagonists have an efficacy of 0
Define affinity
The concentration range within whicha drug binds to a receptor
What is the pA2 value?
An estimate of the concentration of antagonist required to double the concentration of agonist necessary to elicit the original response
