Pharmacodynamics- Receptor Theory Flashcards
What governs the agonists ability to activate a receptor?
Intrinsic efficacy
Which receptor types can the term affinity be used to describe?
Agonists and antagonists, both need to bind with the receptor and affinity describes how easily they do this.
Compare agonists and antagonists
Agonists and antagonists have affinity
Agonists have efficacy as they activate the receptor.
Antagonists lack intrinsic efficacy, they do not activate the receptor- they tend to block endogenous binding.
What measurement is most useful for drug concentration?
Molarity!!!
Grams/L doesn’t explain the number of molecules so is useless.
What is Kd?
Dissociation constant which is a measure of affinity.
low value means high affinity (Km for a drug), note Kd is the reciprocal of affinity.
50% of available receptor sites bound at drug conc Kd
Does it matter how many receptors you have on a cell when determining Kd?
No, because of the law of mass action.
That concentration will occupy 50% of the receptor sites irrespective of the number of sites.
Do we want medication with high or low affinity?
High- means smaller tablets.
Do drug pharmacist represent drug kinetics graphically in the same way as enzyme kinetics are?
No they tend to use logarithm is drug concentration to give a sigmoidal hyperbol from a rectangular hyperbole.
If the number for the loagrithmic drug concentration is negative at 50% binding, what size do you expect Kd to be?
Less than 1.
What is a concentration response curve useful for?
Useful for agonists to look at efficacy and calculate the maximum effect
The concentration of drug that gives half the maximum effect (EC50) or potency
What is the difference between concentration and dose?
If you talk about concentration the assumption is you know the concentration of the site of action ( at the target cells and tissues.) More experimental.
Dose is what you give to someone and the concentration at the target site is unknown.
What factors contribute to the potency of an agonist?
Affinity and efficacy and some cell-tissue specific factors
Potency is the EC50 which is the effective concentration giving 50% of max response.
Describe the pharmacological management of asthma?
Physiology would use adrenaline to relax the muscle contraction by binding B2 receptor (GPCR) in the lungs, in asthma we need to use drugs instead.
Functional antagonism- a drug that antagonises the response with out interacting with the causal pathway.
Which receptor is found in the heart and the lungs?
B1 in the heart- force and rate of heart increases with adrenaline and nor adrenaline binding.
B2 in the lungs- muscle relaxation with adrenaline and nor adrenaline binding
Describe the pharmacodynamic properties of salbutamol.
Affinity 20 times better for Beta 2 found in the lungs (not a big factor difference)
Route of administration and Beta 2 selective efficacy helps utility in asthma treatment.
Salmeterol if a long acting asthma inhaler, describe how it differs from salbutamol?
No selective efficacy in salmeterol with selective affinity( 3455 times). Salbutamol is the opposite
Name a contraindication for salbutamol ( this is the only asthma treatment we have learnt about that you can infuse. Acutely unwell patients who cannot be nebuliser cannot have salmeterol).
Poor selectivity (equal affinity for B1 and B2 receptor) so effects heart- angina patient is a contraindication.
Is salmeterol soluble?
No so it cannot be infused.
Is response proportional to number of receptors?
Often not- there is a maximum response so some receptors aren’t actually contributing if it all the receptors were bound.
Binding curve is to the right of the response curve- why is this important in pharmacodynamics?
Not all receptors must be bound to get maximum response.
Why do spare receptors exist?
Signal amplification and limited post receptor event. A muscle can only contract so much for example. Spare receptors increases sensitivity- low conc of ligand still gets a response.
In lungs smooth muscle what percentage of the receptors binding gives the maximal contraction and why?
10% binding gives Emax.
This is important for ligand sensitivity, lots of receptors allows response at low agonist concentrations. If you bind Kd at any receptor number you need the same concentration but more receptors means 50% binding will bind more receptors which will in turn give a larger response at the same agonist concentration.
Are receptor number fixed?
No they can up and down regulate.
If the cell feels it’s being over stimulated it will remove receptors. This is why chronic pain patients tend to need higher morphine doses after a period of time.
Conversely if cells are under stimulated more receptors will be presented to try and get an effect.
Cells respond to alter effectivity and sensitivity.
List key features of partial agonists:
Lower intrinsic activity giving insufficient efficacy
Endogenous Ligands tend to be full or partial agonists?
Full
Name a side effect of morphine
Respiratory depression
What is the clinical significance of bupremorphine having higher affinity but lower efficacy than morphine?
Bupremorphine has a lower Kd(Higher affinity) but a lower efficacy. Opioid users will get withdrawal on bupremorphine - good to give partial withdrawal and move people off heroin. The receptors are occupied but the effect is lower.
Bupremorphine is less likely to give respiratory depression. It can be used to antagonise heroin.
What 2 factors is partial agonism dependent on?
The compound
The target system (lots of receptors can make it a fill agonist).
Define efficacy clinically.
How good a drug is at producing a response
Do antagonists turn things off?
No they prevent it being switched on.
Name 3 types of antagonists
Reversible competitive antagonism
Irreversible competitive antagonism
Non-competitive antagonism (allosteric or post receptor.)
What is the IC50?
Concentration of inhibitor (antagonist) that gives you 50% inhibition.
What are Kd and KB (pharmacological term) can be used for ?
Measures of affinity for antagonists
Which type of antagonist exhibit surmountable inhibition?
competitive antagonists
Why is surmount ability clinically relevant??
In overdoses you need to compete with the drug and block it binding. Mew opiod receptor inhibited by Naxalone a competitive inhibitor in heroin overdose.
Name an example of a irreversible competitive antagonism.
Pheochromocytoma- a tumour that results in hypertension.
The tumour makes adrenaline which affects the heart and vast smooth muscle.
Phenoxybenzamine which selectively irreversible inhibits the adrenaline at alpha 1 receptors to lower BP
What’s a binding site of an endogenous ligand called?
Orthosteric binding site
Give an example of a site non-competitive antagonists bind to?
Allosteric sites
Allosteric binding sites can effect the receptor in several ways. What result does this have?
Can bind and reduce the affinity or increase the affinity.
Name a HIV drug that acts on chemokine5 receptor 5 on leukocyte to stop HIV binding and internalises the virus.
Maravoric- allosteric modulator to stop viral entry to cells
What is a ligand?
Molecule or ion that binds specifically to receptor
What two actions can drugs have at receptors?
Block endogenous ligand binding - antagoniset
Activate receptor- agonist
What is the efficacy of an agonist?
The ability of an agonist to give a measurable response
What are the advantageous of partial agonist use?
Allow a more controlled response
Work in the absence of endogenous ligand
If lots of full agonist present can act as an antagonist (by blocking receptors but inducing a lower response)
List uses of opiods
pain relief
recreational
How does clopidogrol work?
Prodrug- converted by P450 to a metabolite that irreversibly binds platelet P2Y12- antagonist of thrombosis.
