Dr Podcast Pharmacology Flashcards
What is an agonist?
Agonist is a drug which has significant affinity for its receptor and has full intrinsic activity so when it binds to a receptor, it has a maximum response that the receptor is capable of mediating. This is described as having an intrinsic activity of 1.
What is a partial agonist? (Give clear definition then an example)
A partial agonist is a drug which has significant receptor affinity but only partial intrinsic activity. So unlike a true agonist, when a drug binds to the receptor, a maximum response is never mediated despite an increase in the dose. It is therefore said to have an intrinsic activity between 0 and 1.
An example of a partial agonist is buprenorphine, acting at the mu receptor. Partial agonists can act as either agonists or antagonists depending on the circumstances. If used alone, they are agonists because they produce a response, even if it is not the maximum response the true agonist would produce. They also act as agonists if they are used alongside a low dose of a true agonist. However, if they are used in conjunction with high doses of a true agonist as the same receptor, the partial agonist will act as an competitive antagonist. This is because they will compete with the true agonist at the same receptor, preventing the true agonist from having full occupancy and therefore preventing a maximal response.
What is an inverse agonist?
An inverse agonist is a drug which has significant receptor affinity and intrinsic activity, but it exerts an opposite effect to the endogenous agonist. An example is atropine and acetylcholine at the muscarinic receptor.
What is an antagonist?
An antagonist has significant receptor affinity but has no intrinsic activity. So when a drug binds to a receptor, no response is mediated. Antagonists are therefore described as having an intrinsic activity of zero.
What different types of antagonists do you know about?
Antagonists can be described as reversible or irreversible.
Reversible antagonists can be further sub classified as competitive or non-competitive.
Reversible competitive antagonists are competing for the same receptor as the antagonist. This means that the effect of the antagonist can be overcome by increasing the dose of the agonist. Examples of competitive antagonists include non-depolarising muscle relaxants, which compete for the nicotinic receptor in the neuromuscular junction. Beta-blockers which compete with adrenaline at the beta-adrenergic receptor sites in the heart.
Reversible non-competitive antagonists do not bind to the same receptor site as the agonist nor do they alter binding of the agonist. Instead, they prevent receptor activation through conformational distortion of the receptor. Because they are non-competitive, their action cannot be overcome by increasing the concentration of the agonist. An example of a reversible non-competitive antagonist is ketamine, with antagonises glutamate at the NMDA receptors in the CNS.
Irreversible antagonists bind irreversibly to the receptor or distant site and prevent the agonist binding to their receptor. With irreversible antagonism, increasing the dose of the agonist will not overcome the blockade because the antagonist is bound irreversibly. An example is phenoxybenzamine, which binds irreversibly to the alpha adrenoceptors, antagonising the effects of alpha catecholamines.
What is the difference between a competitive antagonist and an inverse agonist?
The difference between an inverse agonist and a competitive antagonist is important. An inverse agonist will exert its own physiological effect, the opposite of the agonist when it binds with the receptor. Whereas an competitive antagonist has no direct effect of its own, but simply stops the endogenous agonist exerting its effect.
What is the dose response curve?
PICTURE
The dose response curve is a graph with the concentration of the drug on the x-axis and with the response on the y axis. It is hyperbolic in shape. This graph shows that as the drug concentration increases initially, the receptor occupancy increases dramatically. So accordingly, the response increases dramatically. However, when the number of empty receptors decreases, increasing the concentration of the drug has a smaller effect on the response illicited, so the slope of the curve flattens out completely at 100%.
On a dose response curve, when the dose of the agonist is 0, the response will also be zero.
In addition, the maximum response, or intrinsic activity will always be 1.
The drug concentration where 50% of the receptors are occupied is the Ka value (acid dissociation constant).
What is a log dose response curve? What are it’s advantages?
PICTURE
The log-dose response curve is a semi-logarithmic plot. The curve is plotted using a logarithmic scale for the dose on the x-axis and response on the y axis.
Unlike the hyperbolic shape of the dose response curve, this produces the classical sigmoid shaped curve. The hyperbolic shape of the dose response curve makes it difficult to identify the maximum response and also makes it hard to make comparisons with other agonists and antagonists. In contrast, when using the log dose response curve, the steep part of the curve is approximately linear. This makes the assessment of the relationship between dose and response easier to understand. The Ka value, where 50% of the receptors are occupied is on the steep linear part of the curve.
How would the curve for a drug with a lower potency compare to a drug with a higher potency?
The potency of a drug would cause a parallel shift of the curve to the left or the right.
A more potent drug would cause a shift to the left, because lower concentrations of the drug are required to produce the same response.
A lower potency drug would cause a shift in the graph to the right, as higher concentrations of the drug are required to cause a similar response.
The maximum response of both of the drugs will be the same, so the height of the curves will be the same.
What else would make the log dose response curve move the right? (Apart from different potency)
If a competitive antagonist is given alongside a full agonist, this will also cause a parallel shift of the curve to the right. This is because a higher concentration of the agonist is then required to produce the same response because it is competing with the antagonist.
What would happen to the shape of the log dose response curve if a non-competitive antagonist is given?
If a non-competitive antagonist is given, such as ketamine, the log-dose curve will move to the right, and in addition, the maximum achievable response is reduced. This is because with non-competitive antagonists even increasing the dose of the agonist will not overcome the effects of the antagonist, and therefore the maximum response can never be achieved.
What would happen to the shape of the log dose response curve if the drug is a partial agonist?
If a partial agonist is given, there is no parallel shift in the curve, but it will be impossible to elicit the maximum response despite high drug doses so the height of the curve will be smaller.
What is the dose ratio?
Term used to describe the extent of the right-ward shift of the log-dose response curve in the presence of a competitive antagonist. It is used to determine the factor by which the dose of the agonist must be increased to produce a maximal response in the presence of a competitive antagonist.
What do you understand by the terms “affinity and intrinsic activity”?
Affinity is how avidly the drug binds to its receptor, or how well the key fits in the lock.
Intrinsic activity aka efficacy is the magnitude of effect that the drug produces after it has bound to the receptor.
