Pharmacodynamics Flashcards
What is the law of mass action?
L+RRL
Binding of ligand to receptor is an equilibrium so more ligands present shifts equilibrium to right.
What is an antagonist?
A molecule which blocks the binding of an endogenous agonist.
What is an agonist?
A molecule which activates a receptor
What is intrinsic efficacy?
The ability of the ligand to activate the receptor
What is efficacy?
The ability of a ligand to cause a response
How do we measure drug receptor interactions by binding?
Bind radioactively labelled ligand to cells or membrane prepared from cells
A graph can be drawn of proportion of receptors bound vs drug concentration
What is Kd?
The concentration at which half of the receptors are occupied
It is therefore an index of affinity
Lower value=higher affinity
Why is a low Kd important for drugs?
Allows binding at low concentrations so we dont have to give huge amounts of drugs to patients
What is EC50?
The effective concentration giving 50% of the maximal response?
What is the difference between ‘concentration’ and ‘dose’?
Concentration =known concentration of drug at site of action
Dose=concentration at site of action unknown eg, amount given to patient
What is EC50 a measure of?
POTENCY- depends on both affinity and intrinsic efficacy, plus cell specific components that allow something to happen eg. Number of receptors
How does adrenaline act as a functional antagonist
It activates B2 adrenoceptors which counteract the contraction of the bronchioles (counteract function so functional antagonist)
Why might there be a problem in treating athsma via B2 adrenoceptors? Why is this sometimes ok?
There are B1 adrenoceptors in the heart which increases force and rate which could cause a heart attack to someone with angina, so we need specific activation of B2 adrenoceptors.
How is salbutamol selective to B2 receptors and how good is this selectivity?
B2 selective efficacy and route of administration- in other words, it has a slightly 20 fold higher affinity for B2, and is more effective at creating response.
Selectivity is poor as only slightly higher affinity
Route of administration (i.e via lungs)
Why is salmeterol selective to B2 adrenoceptors?
Much higher affinity, no selective efficacy
Why do spare receptors exist and why are they useful?
Exist because of:
-amplification in signal transduction pathway
Response limited by a post receptor event.
Why- increases sensitivity, makes it easier for Kd to be reached because receptor ligand binding depends on mass action law
What does changing receptor number do?
Changes agonist potency and affects maximal response
How is receptor number altered?
Up regulation with low activity
Down regulation with high activity
For drugs this can contribute to tolerance /tachyphylaxis
What is a partial agonist?
One with a lower intrinsic efficacy so more receptors must be occupied by agonist to produce maximal response
How can partial agonists act as antagonists and what is an example of this?
Sits in sites but produces a lower response , buprenorphine produces less of a high than morphine but blocks morphine having an affect so less harmful- used to wean patients off drug
If an addict accidentally injects this then will experience withdrawal symptoms
How can a partial agonist stimulate a full response?
If it binds to enough receptors it can stimulate 100% response even though it has lower efficacy
What is IC50?
The concentration of antagonist giving 50% inhibition
What does surmountable inhibition?
The inhibitor can be out competed by adding more agonist
Which way to reversible competitive antagonists move the concentration response curve?
Adding antagonists move the curve to the right
How can competitive inhibition be used clinically in treatment of opioid mediated respiratory depression?
Haloxone is a high affinity competitive agonist at mu opioid receptors to competes with other opioids for receptors and stops them binding.
What effect do irreversible competitive antagonists have on the shape or position of the agonist response curve?
Move it to the right then suppress maximal response as spare receptors run out.
How can irreversible competitive antagonists be used clinically?
Used in treatment of pheochromocytoma- tumour in kidney produces too much insulin which causes constriction of blood vessels and therefore hypertension
Phenoxybenzamine is used to irreversibly inhibit binding sites of alpha 1 adrenoceptors so adrenaline cannot bind and cause blood vessel contraction.
What is the site called at which endogenous ligands bind to GPCRs?
The Orthosteric site
What is the effect of non competitive antagonism?
What is an example of a drug which uses this?
No competition for binding site so reduce orthosteric ligand affinity and or efficacy - similar pharmacological effects to irreversible competitive antagonism
Maraviroc- negative allosteric modulator of chemokine receptor 5 which is used by HIV to enter cells so is used in AIDS treatment.
