PHAR1: Introduction - pharmocodynamics Flashcards
What is pharmacodynamics?
what the drug does to the body
What is pharmacokinetics?
what the body does to the drug
What are the four types of drug targets?
- Receptors
- Enzymes
- Ion channels
- Carrier proteins
Where do aspirin, anaesthetics, Prozac and nicotine have their effect?
aspirin -> binds to the enzyme cyclooxgygenase and blocks the production of prostaglandins
anaesthetics -> block sodium ‘ion channels’ and thus prevent nerve conduction
prozac -> blocks serotonin
nicotine -> binds to and activates the nicotinic acetylcholine
What are the major structural differences between dopamine, noradrenaline and serotonin?
- Noradrenaline has a hydroxyl group extra than dopamine
- Serotonin is similar to dopamine but possesses an indole ring with one hydroxyl group instead of a benzene ring with hydroxyl groups. It does possess the same ethyl side chain with one amine group.
Because dopamine, noradrenaline and serotonin all have a similar structure what does this mean?
They all have some degree of specificity for the other receptors
What is the main problem when molecules have some affinity for other molecule’s receptors?
Side effects due to unspecific binding
What is Pergolide?
A parkingson’s disease drug
For Pergolide, what are the different effects induced at different concentrations?
0.4nM: therapeutic effect (D2 receptor target)
5nM Hallucinations (5HT2B Receptor - serotonin)
40nM: Hypotension (alpha1 receptor - Adrenergic)
Why does the effect become less specific as the concentration of the drug increases?
Because Pergolide starts to interact with other drug targets producing other unwanted effects.
What does therapeutic window mean?
What is it for?
A concept linked to drug target selectivity and dose This provides an indication of the safety of the drug.
What quantifies the therapeutic window?
The therapeutic index
What does the therapeutic index do?
Compares the dose of a drug that produces therapeutic effect with the dose of the drug that produces a toxic effect
How do you measure the therapeutic effect?
ED50 – the effective dose to produce a specific therapeutic effect in 50% of the population.
Or 50% of maximal response
How do you measure the toxic effect?
TD50 – the dose required to produce a specific toxic effect in 50% of the population
How do you calculate therapeutic index?
Therapeutic index = TD50 / ED50
The higher or lower the therapeutic index the better?
The higher = the safer the drug
If you were to increase the concentration of the drug, what happens to the drug receptor complex equilibrium?
It is strongly shifted to the right - this is because there is more drug available to bind to free receptors.
If you were to dramatically reduce the amount of drug available what happens to the shift in equilibrium?
Then more receptors would become available again due to the lower drug concentration. This shifts the equilibrium to the left.
What does affinity mean?
Determines the strength of binding of the drug to the receptor
Why is affinity is strongly linked to receptor occupancy?
The strength of each drug-receptor complex is determined by the affinity of the drug
If two drugs are present in a tissue then why would a drug that has a higher affinity, at any given moment have more of its molecules bound to receptors?
It will form stronger drug receptor complexes and thus at any given moment, it is more likely that more of this drug will be bound to receptors.
What does efficacy refer to?
The ability of an individual drug molecule to produce an effect once bound to a receptor
How must an agonist act?
An agonist must possess affinity i.e. the ability to bind to the specific receptor and efficacy i.e. the ability to activate the receptor once bound.
Can an exogenous or endogenous drug be delivered to its target location more precisely?
endogenous
What is an antagonist?
It has affinity for the receptor but zero efficacy
What happens to the log dose response curve eventually? Why?
It levels off, because you reach the maximum tissue response
What shape do all agonist dose response log curves have?
Sigmoidal shape
What is it important to remember about agonist/antagonist - receptor interactions?
It is very transient
What is a full agonist?
100% response can be achieved: each drug molecule when bound to a receptor can simulate the maximal response from that individual receptor (full efficacy). Once enough receptors are bound and activated, the maximal tissue response can be achieved
What are partial agonists?
Each drug molecule when bound to a receptor CANNOT stimulate the maximal response from that individual receptor (partial efficacy)
When a large number of receptors are bound and activated by partial agonists, will the maximal tissue response be achieved?
No the maximal tissue response can never be achieved
Where will the partial agonist dose-response curve be in comparison to the full agonist?
Below
What is a competitive antagonist?
Blocks the receptor transiently: it can only bind to and block a receptor for a brief period of time. It then detaches from the receptor and is then available to bind to and block another receptor.
What is an irreversible receptor agonist?
It produces a long term (possibly permanent) blockade of the receptor. Therefore, for every molecule of irreversible antagonist bound to a receptor, there is one less receptor available to bind the agonist.
If the agonist and competitive antagonist are both present in the tissue, and you increase the concentration of the agonist, will you be able to outcompete the competitive antagonist for receptor spaces?
There will be more molecules of agonist present to out-compete the antagonist. Therefore, the blockade produced by the competitive antagonist is surmountable, as the agonist and antagonist are constantly ‘competing’ for free receptors.
If the agonist and irreversible antagonist are both present in the tissue, and you increase the concentration of the agonist, will you be able to outcompete the irreversible antagonist for receptor spaces?
Once that individual receptor is blocked, increasing the dose of agonist will have no effect on that particular receptor. Also increasing the agonist will not necessarily increase the response, since the agonist cannot compete with molecules of antagonist that have already bound to and blocked receptors.
If a competitive antagonists and agonists are present in the tissue then what will happen to the response in a dose-response log curve?
Lower level of response, because some of the receptors will be blocked by antagonists at any one time
If a competitive antagonists and agonists are present in the tissue but you increase the dose of the agonist, then what will happen to the response in a dose-response log curve?
Absolute paralelle shift to the right compared to the curve with no antagonist, (increased dose hence shift to right) but the response can still reach horizontally equal to the response with no antagonist present. Restore the level of response. You can always over compensate.
If a irreversible antagonists and agonists are present in the tissue but you increase the dose of the agonist, then what will happen to the response in a dose-response log curve?
Lower sigmoidal curve, the more irreversible antagonist you add the lower the curve gets, eventually you can get a flat line with no response. You cannot outcompete the irreversible antagonist with more agonist.
What is potency
Potency is related to dose. The less drug you require to produce a particular effect, the more potent the drug is.
What is used to compare potency?
ED50
the difference between a partial agonist and a full agonist is a difference in ______.
Efficacy
A highly potent drug produces a large response at relatively ___ concentrations
low
A highly efficacious drug can produce a ______ response and this effect is not particularly related to drug concentration
maximal
Which is more important between efficacy and potency?
Efficacy - You want to know if the drug you are giving can induce a maximal response. The potency simply determines the dose that you will need to administer to produce a response.
