Receptor Theory Flashcards
What are the 2 principle theories for nerve impulse transmission across the gap at synaptic/neuroeffector junctions?
Electrical
Humoral (chemical)
Perfused Frog Heart Experiments
First evidence of chemical transmission
1. The vagus nerve of a frog heart was electrically stimulated, resulting in slowing of the heart
2. The fluid surrounding the heart was pumped to a second frog heart without a vagus nerve
3. The second heart slowed down! (with no electrical stimulation)
This experiment was also repeated with stimulation of the accelerans nerve in heart 1, leading to an increase in the rate of heart 1 and 2
What was the conclusion drawn from the ‘Perfused Frog Heart Experiments’?
Heart 1 released a chemical substance (vagusstoff/acceleranstoff) from the endings of its vagus/accelerans nerve that was conveyed to the heart 2 in the fluid
Vagusstoff
Acetylcholine
Acceleranstoff
Noradrenaline
Physostigmine
Potentiates acetylcholine by inhibiting cholinesterase
Pharmacokinetics
What the body does to the drug
Pharmacodynamics
What the drug does to the body, i.e. the relationship between the drug concentration at the site of action and the resulting effect
Receptor
A macromolecule with which a drug combines to produce its characteristic effects
A molecular structure on the surface or interior of a cell that binds substances e.g. hormones, neurotransmitters, drugs
Example of a ligand-gated ion channel
Nicotinic receptors
Examples of GPCRs
Muscarinic receptors, adrenoceptors
Example of kinase-linked receptor
Insulin
Example of nuclear receptor
Steroid
EC50
The concentration of drug that elicits 50 % of the max response
Can only be calculated for AGONISTS
pEC50
Negative logarithm of EC50
= pD2
Intrinsic efficacy
The capacity of a drug to initiate a response at the receptor
Different molecules have…
…different capabilities at inducing a physiological response
Antagonist
A drug that binds to a receptor but elicits no response and blocks the responses induced by agonists
i.e. antagonists have affinity for a receptor but no efficacy
Partial agonists
Exhibit some agonist activity at a receptor but fail to elicit the full response
Block the responses induced by full agonists as the receptor
Alpha
= intrinsic activity
alpha = 1 = full agonist
alpha = 0 = full antagonist
0 < alpha < 1 = partial agonist
Affinity
The strength of the interaction between a drug and a receptor, controlled by thermodynamic forces (drug will reside in a pocket of “minimal free energy”)
The affinity of a drug for a receptor can be modelled by…
… the Langmuir Adsorption Isotherm
Langmuir Adsorption Isotherm
The model for affinity
Ka
= dissociation constant (K2/K1) => a concentration! The concentration of drug that binds to 50 % of the total receptor population, i.e. p = 0.5 when [A] = Ka
Langmuir equation
p = [AR} / [Rt} = [A] / [A] + Ka
A smaller Ka value means…
…higher affinity. Higher fraction of receptors are bound. Affinity is the reciprocal of Ka (because Ka is a DISsociation constant, not ASsociation)
p =
= fraction of maximal binding.
Receptor reserve
The receptors that are not required for a maximal response
What is the magnitude of the receptor reserve dependent on?
The agonist’s efficacy at the receptor
Examples of receptors with constitutive levels of activity
Cannabinoid, dopamine, GABAA (BZ receptors)
Two-state model of receptor activation
Agonists have a higher affinity for R* (receptors in their active state)
Inverse agonists have a higher affinity for R (receptors in their inactive resting state)
What are the 5 mechanisms of drug antagonism?
Antagonism by receptor block (reversible/irreversible) Non-competitive antagonism Chemical antagonism Pharmacokinetic antagonism Physiological antagonism
Reversible competitive antagonism by receptor block
Leads to parallel shifts in dose-response curves
Increasing agonist concentration will restore receptor occupancy - “surmountable”
Maximal response can still be achieved
Antagonist has a high rate of dissociation and can be displaced by the agonist
Irreversible competitive antagonism by receptor block
Leads to decreased maximal response on dose-response curve
Antagonist only dissociates very slowly from the receptor and there is no change in antagonist occupancy when the agonist is applied
How might an irreversible competitive antagonist produce a parallel shift in a dose-response curve? i.e. the same effect as a reversible competitive antagonist
For a full agonist with low receptor occupancy (i.e. < 5 %) for maximum response, then > 95 % of receptors must be blocked by the antagonist before the maximal response is reduced
Therefore low concentrations of an irreversible competitive antagonist will only lead to a parallel shift in the dose-response curve
Non-competitive antagonism
The antagonist blocks the chain of events after an agonist has bound that lead to the evoked response
e.g. nifedipine = Ca2+ channel blocker, so prevents Ca@+ influx which produces a non-specific block of smooth muscle contraction induced by ACh
Chemical antagonism
When two drugs combine in solution so that the effect of the active drug is lost e.g. to counteract overdose of one drug
Examples of drugs that are typically irreversible competitive antagonists.
Drugs with reactive groups that can form covalent bonds with the receptor e.g. aspirin
Pharmacokinetic antagonism
When one drug reduces the concentration of an active drug at its site of action e.g. through increasing its rate of metabolism/changing rate of absorption/renal excretion
Physiological antagonism
The interactions of 2 drugs with opposing actions that cancel each other out, helping to maintain homeostasis
Examples of physiological antagonism
Noradrenaline increase blood pressure, ACh decreases blood pressure
Dose ratio
The ratio by which the agonist concentration needs to be increased in the presence of a reversible competitive antagonist to elicit the same response
Key points of the humoral (chemical) theory
Transmission across the gap is uni-directional ad occurs with a slight delay
Fatigue occurs more readily junctions because transmission is limited by the number of vesicles
Drugs may selectively act at synapses/junctions
Total area available for binding
1
Area already bound
Theta
Area available for binding
1 - theta
Alpha (LMI)
Characteristic rate of diffusion of a molecule towards a surface (condensation)
V
Characteristic rate of dissociation of a molecule from a surface (evaporation)
Mu
Concentration of drug in the medium
Rate of adsorption
alpha x mu x (1-theta)
Rate of dissociation
Vtheta
Theta
(alpha x mu) / [(alpha x mu) + V]
Law of Mass Action
The rate of reaction is proportional to the product of the concentrations of the reactants
Schild equation
log(DR-1) = log[B] - logKb
When DR = 2, [B] = Kb
Kb
= antagonist dissociation constant
pA2
= -log[B], where [B] is the concentration of antagonist where twice the concentration of agonist is required to elicit the same response as the agonist alone
= log(DR-1) - log[B]
What do similar pA2 values in different tissues indicate?
Identical receptors
What does it mean if the slope of a Schild plot = 1?
The antagonist is competitive
Write out derivation of the Schild equation
:)
Axes on Schild plot
x axis = log[antagonist]
y axis = log(DR-1)
