Lecture 17 - Pharmacodynamics Flashcards
What is a ligand?
Chemical/molecule which binds to a receptor
What happens when a ligand binds to a receptor?
Causes conformational change
Signal transduction
Response produced
What type of drug is Salbutamol?
B2 selective agonist
What does Salbutamol treat?
Asthma
What type of drug is Bisoprolol?
B1 selective antagonist
What can Bisoprolol treat?
Hypertension
Angina
What type of drug is co-codamol?
Mu -opioid receptor agonist
What is co-codamol used for?
Analgesic
What type of drug is Atorvastatin?
HMG-CoA reductase inhibitor
What is Atorvastatin used to treat?
Dyslipidemia
What are the units, Molar, Millimolar, micromolar and nanomolar?
mM = 10^-3 0.001M
Micromolar = 10^-6 0.0000001
nM = 10^-9
Why is concentration of drug molecules around receptors critical in determining drug action?
Low concentration means receptor less likely to be activated
Do most drugs associate permanently or reversible with receptors?
Most bind reversibly
What is an agonist?
Ligand that binds to the receptor activating it
What is an antagonist?
A ligand/drug that blocks a receptor preventing an agonist binding to the receptor
Agonists and antagonists for receptor have an affinity for that receptor.
What is meant by affinity?
The liking/attraction for a ligand to bind to a receptor
What is intrinsic efficacy?
Ability for a ligand to change a receptors shape to activate it
(R*) = activated receptor
Describe an agonist in terms of affinity and intrinsic efficacy:
Has Affinity for the receptor
Has Intrinsic efficacy (so activates receptor)
Describe an antagonist in terms of affinity and intrinsic efficacy:
ONLY has Affinity for receptor
NO INTRINSIC EFFICACY (Doesn’t activate receptor)
What is clinical efficacy?
How well a treatment succeeds in completing its aim
What is Efficacy?
Takes into account intrinsic efficacy and the things that happen that lead to the desired therapeutic response
What is Bmax?
Bmax = Maximum Binding Capacity
When all receptors have ligands bound to them
What is Kd?
The concentration of the drug which causes 50% occupancy of ligands bound to receptors
(Conc when 50% of receptors have ligands/drugs bound)
The dissociation constant
What does the value of Kd actually indicate?
The affinity/strength of interaction of the ligand and the receptor
If a ligand has a high Kd value what does this indicate?
If a ligand has a low Kd value what does this indicate?
High Kd = Low affinity (more drug needed to reach 50% occupancy)
Low Kd = High affinity (less drug needed to reach 50% occupancy)
Why is it useful for drugs to have a high affinity for a receptor? (Low Kd value)
Smaller amounts of drugs can be given
What occurs to the respiratory system as a result of a heroin or morphine overdose?
Respiratory depression
Then death
How does Naloxone treat a heroin overdose?
Antagonist to mu opioid receptor
Naloxone outcompetes the opioid
What must a drug have in order to cause a response when bound to a receptor?
Efficacy
What is Emax?
The maximum response that can be reached
What is EC50?
(Effective concentration giving 50% of maximal response)
The concentration of drug needed to reach 50% of the maximum response
What does the value of EC50 indicate?
Drug potency
What is Potency?
The amount of a drug needed to cause a response (Describes response not binding
What does potency depend on?
Affinity
Intrinsic efficacy
Cell/tissue-specific component that allow for the response to happen
What is concentration of drug at a drug site?
When the concentration of a drug at a site of action is KNOWN
What is dose of a drug at a drug site?
When the concentration of a drug at a site of action is UNKNOWN
Give an example of functional antagonism:
When treating asthma give a B2 adrenoceptor agonist
This apposes the pathological bronchoconstriction causing smooth muscle to Releaf (bronchodilation)
In treating asthma why does the Beta 2 adrenoceptor agonist need to be selective/specific?
Don’t want to stimulate B1 adrenoceptors in the heart (unwanted +ve chronotropy, +ve inotropy)
Describe the selectivity of Salbutamol for B2 receptors in terms of affinity and efficacy:
Has high affinity for B2 receptors
High selective efficacy for B2 compared to B1
Selectivity is based on its B2 selective efficacy
Describe the selectivity of Sameterol for B2 receptors in terms of affinity and efficacy:
High affinity for B2 receptors
Selectivity based on affinty not selective efficacy
Why can Salmeterol not be administered via IV?
Insoluble
What are spare receptors?
When there are receptors that dont additionally contribute to a response
(When the response is limited by other factors)
What is the relationship between EC50 and Kd in order for there to be spare receptors?
EC50 < Kd
Means that the concentration of the ligand in order to produce the max response is less that the concentration needed to occupy all receptors
What causes Spare receptors to exist?
Amplification in the signal transduction pathway
Response is limited (muscle can only contract so far)
What is the benefit of having spare receptors?
Increase sensitivity/potency
Meaning lower concentrations of agonist is required for full response
What can receptor number influence?
The sensitivity to the agonist
Maximal response (may not be enough receptors for the maximum response to actually be reached)
What affects the number of receptors on a cell?
Cell type
Increases with low activity (Up regulation)
Decreases with high activity (Down regulation)
Why do people need higher doses of morphine the more they have it?
The mu opioid receptors become internalised the more they are used (Down regulation)
Means less morphine can bind
What is a full agonist?
An agonist that will produce a maximum effect/response when theres full occupancy
What is a partial agonist?
An agonist that is unable to produce a maximum affect even with full occupancy
What has a higher potency, a full agonist or partial agonist?
Full agonist
What is happening in terms of efficacy for partial agonists?
Insufficient intrinsic efficacy (LOWER THAN FULL AGONISTS) for maximum response to be reached
What is meant be the EC50 for a partial agonist?
The concentration of the drug needed to to reach 50% of its response (Not the maximum response)
How does a larger response relate to intrinsic activity/efficacy?
Larger response = Greater intrinsic activity/efficacy
How can you make a partial agonist become a full agonist?
Increase the number of receptors
How can partial agonists act as drugs?
They can act as antagonists by binding to receptors and preventing a full response from occurring (prevent full agonists binding)
Heroin is an opioid, what is used to treat a heroin overdose?
Buprenorphine
How does buprenorphine treat heroin overdose?
Is a partial agonist
Binds to mu opioid receptors giving a little high but preventing maximum response preventing RESPIRATORY DEPRESSION and Death
How do antagonists generally work?
Block effects of agonists be preventing them from binding
What are the 3 types of antagonism?
Reversible competitive antagonism
Irreversible competitive antagonism
Non-competitive antagonism (usually Allosteric)
What is the principle of reversible competitive antagonism?
Relies on the antagonist out competing the agonist for the binding site
They do associate and deassociate
What is IC50?
Inhibitory Concentration 50
The concentration of inhibitor which inhibits 50% of the maximal response
What factors affect the inhibition from a reversible competitive antagonist?
Antagonists Affinity
Concentration of Antagonist
Concentration of the agonist
What can happen if the concentration of the agonist increases but the competitive reversible antagonist does not?
Agonist can outcompete the antagonist so the inhibitory effects can be over come
What happens to the concentration response curve with a reversible competitive antagonist?
Same height shifts to the right
(Maximal response can still be achieved it just happens at a higher concentration of agonist
What is a drug which treats heroin OD that is a competitive antagonist?
Naloxone
What receptors does Naloxone bind to preventing heroin from binding?
Mu opioid receptors
What is Irreversiible competitive antagonism?
When the antagonist dissociates very slowly or not at all
Can increasing the [agonist] overcome the effect of irreversible competitive antagonism?
No since the receptors all remain blocked
How do irreversible competitive antagonists affect the response [agonist] curve?
Initially just shift curve further right
Then as [antagonist] increases max response decreases since the spare receptors get inhibited
What is Phaeochromocytoma?
Tumour of adrenal chromaffin cellls leading to excesss adrenaline/noradrenaline secretion
What is Phaeochromocytoma?
Tumour of adrenal chromaffin cellls leading to excesss adrenaline/noradrenaline secretion
What drug can be given to treat Phaeochromocytoma to act on A1-adrenoceptors?
What drug can be given to treat Phaeochromocytoma to act on B1-adrenoceptors?
Phenoxybenzamine
Bisoprolol
What does the excess adrenaline acting on A1 adrenoceptors cause?
Vasoconstriction
Hypertension
Headache
Sweating
Panic attacks
What type of antagonist is clopidogrel?
Irreversible competitive antagonist
What does clopidogrel do?
Reduce platelet activation preventing thrombosis
What is non competitive antagonism ?
When a ligand binds to a site on the receptor that is not the active site/orthosteric site
This reduces the orthosteric ligands affinity for the active/orthosteric site
What is the site called which a non competitive inhibitor will bind to?
Allosteric site
How can Maraviroc be used with HIV treatment?
Binds to receptors Allosteric site
Conformational change of receptor prevents viral ability to bind to receptor
Prevents virus entry into cell
