Efficacy vs. Potency - Pharmacology - Medbullets Step 1
Potency is the concentration (EC50) or dose (ED50) of a drug the exam candidate to "define and explain dose-effect relationships of drugs. In the field of pharmacology, potency is a measure of drug activity expressed in terms of the Efficacy is the relationship between receptor occupancy and the ability to The concentration of A at which E is 50% of Emax is termed the half maximal effective concentration and is abbreviated [A]50, or more commonly EC The concepts of IC50 and EC50 are fundamental to pharmacology. one to quantify the middle of the curve (the drug's potency) and one to.
This results in a flow of channel permeant ions e. Na and K for nicotinic receptors down their electrochemical gradient with a resultant change in membrane potential Figure 5. In skeletal muscle, this results in a depolarization of the membrane potential, the production of an action potential, and contraction the biological response.
G-protein activation of an ion channel The drug receptor stimulates an ion channel via activation of a G protein Figure 6.
- Efficacy vs. Potency
- Potency (pharmacology)
- 50% of what? How exactly are IC50 and EC50 defined?
As an example, this is the mechanism by which acetylcholine acts to slow the heart rate. G-protein activated ion channel. Binding of an agonist to the m2 receptor activates a G-protein Gi which in turn stimulates a K-selective channel to open.
The increase in K permeability will hyperpolarize the membrane potential. G-protein activation of a second messenger cascade There are two well characterized second messenger cascade mechanisms. One involves the G-protein Gs mediated activation of adenylyl cyclase, with subsequent formation of camp and activation of protein kinase A PK-A Figure 7.
DAG acts as a second messenger to stimulate protein kinase C, and IP3 stimulates the release of Ca ions from intracellular stores. DAG acts as a second messenger to activate protein kinase C PK-Cwhich phosphorylates a variety of intracellular proteins.
IP3 stimulates the release of Ca from intracellular stores. These mechanisms are believed to mediate the vasoconstrictive effects of Ang II on vascular smooth muscle. Receptors linked to Cytoplasmic Enzymes e. These receptors contain an extracellular domain that binds to a specific ligand, and a cytoplasmic domain that typically contains a protein tyrosine kinase Figure 9.What is DOSE-RESPONSE RELATIONSHIP? What does DOSE-RESPONSE RELATIONSHIP mean?
However, other enzymes such as serine kinases, or a guanylyl cyclase may also be coupled to a receptor and work by the same mechanism.
EGF, Insulin, various growth factors Figure 9. The binding of a ligand to receptors produces a change in receptor conformation that allows receptors to interact. The auto-phosphorylation typically results in a prolonged response to the agonist e. Noncompetitive Antagonists Antagonists are drugs that bind to receptors have affinitybut do not produce a substantial degree of receptor stimulation they have very low efficacy.
Antagonists are typically classified as competitive or noncompetitive. Competitive antagonists bind reversibly to the same receptor site as the agonist. This effect produces a rightward parallel shift of the dose-response for the agonist towards higher concentrations.
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In the presence of a competitive antagonist, agonists can still produce the same e. The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists. Noncompetitive antagonists either bind irreversibly e. The primary effect of a noncompetitive antagonist is a reduction in the maximal effect produced by the agonist see Figure 10B.
In some cases the slope may also be reduced. In contrast to a competitive antagonist, the effect of a noncompetitive antagonist cannot be reversed by simply increasing the concentration of the agonist, since the law of mass action does not apply.
Examples of Competitive and Noncompetitive Antagonism. In the presence of the competitive antagonist, the dose-response curve is shifted to the right in a parallel manner. This reduces the fraction of available receptors, and reduces the maximal effect that can be produced by the agonist. Under physiological conditions, the level of such spontaneous activity is relatively low, and is not easily observed unless the wild-type receptor is cloned and over-expressed e.
More recently, several naturally occurring mutant GPCRs with increased constitutive activity have been identified. Interestingly, recent research using a mouse model of heart failure indicates that mechanical stretch, such as that caused by heart failure, enhances the constitutive activity of cardiac angiotensin II receptors, resulting in the development of cardiac remodeling hypertrophyindependent of Angiotensin II stimulation.
Furthermore, this harmful effect contributing to cardiac remodeling can be reversed by treatment with the AT1 receptor inverse agonist candesartan Yasuda et al, Whether this mechanism contributes to the well documented harmful effects of angiotensin-II in patients with heart failure, as well as the beneficial effects of angiotensin receptor antagonists in heart failure including candesartanis yet to be clearly documented.
Figure 12 illustrates proposed models of drug-receptor interaction for receptors exhibiting an absence of constitutive activity, and for receptors that are spontaneously active in the absence of ligand. Drugs that selectively stabilize the inactive receptor conformation Di act as inverse agonists when they bind to constitutively active receptors, due to their ability to reduce the degree of basal activity. In the absence of basal activity e. Drugs that selectively stabilize the active receptor conformation e.
Drugs that bind non-selectively equally to both receptor conformations behave as classical antagonists. Physiological antagonism involves drug activation of two different compensatory biological mechanisms that exist to maintain homeostasis by different mechanisms. Acetylcholine and norepinephrine exert their effects through different receptors and signal transduction pathways, which when activated produced opposing effects e.
Chemical antagonism occurs when a drug reduces the concentration of an agonist by forming a chemical complex e. Pharmacokinetic antagonism occurs when one drug accelerates the metabolism or elimination of another e.
Drugs often work on multiple receptors Drugs often work on more than one receptor, and as a result produce more than one kind of biological response Figure One good example is norepinephrine NEthe sympathetic neurotransmitter which can relax bronchial smooth muscle, but constrict arterial smooth muscle.
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A single drug can interact with multiple receptors. These receptors are coupled to different intracellular messenger systems, and produce different responses when stimulated. These receptor subtypes are not typically expressed in equal amounts in the same tissue e.
Selectivity, and the Therapeutic Window If a drug has one effect, and only one effect on all biological systems it possesses the property of specificity. In experience, the vast majority of drugs are selective rather than specific. This is the case because most drugs will act on more than one receptor site once they reach an appropriately high concentration. The concentration range over which a drug produces its therapeutic effect is known as its therapeutic window. Similar to most drugs, yohimbine lacks true specificity in its biological actions.
EC50 — used for in vitro studies only When investigating drug effects in a tissue bath setting, drug concentrations are typically precisely known. An example of an exception to this rule is when one is using an impure source of a drug e. In this case the total dose gram weight of St. John's wort used would be more easily defined vs the concentration of the active ingredient swhich may be unknown.
The concentration of drug achieved in the bloodstream e. As a result, in whole animal experiments, we talk of doses that produce a given magnitude of therapeutic effect, e.
One can also define how drug responses vary in a population of animals or patients. In this situation, one can define the minimum dose needed to produce the desired effect in each animal or patient. The results of this type of study can be plotted in the form of a quantal dose response curve Figure To summarize, ED50 is a value defined in whole animal or population studies. In contrast, if the discussion concerns drug responses in a population, ED50 will most likely indicate the median dose producing the desired therapeutic effect e.
Drug responses can also be defined as quantal. An illustration of a quantal dose-response relationship is shown in Figure 14, which depicts the relationship between the dose of a drug vs.
With a sufficiently large patient population, this type of relationship is often well-fit by a Gaussian distribution, in which statistical parameters can be used to predict the variability of drug response in the patient population.
This type of dose-response relationship is most useful for defining quantal events such as the prevention of convulsions, arrhythmia or death by a drug. A set of data obtained after administration of increasing doses of a drug to a group of patients, and observation of the minimum dose at which each patient responded with the desired outcome.
The results have been plotted as a histogram, and fit with a gaussian curve. The dose-relationships for toxic and lethal effects may have different slopes compared to therapeutic dose-response relationship because they produce effects by different receptors or mechanisms e. It is of value to know the relative difference between the average toxic dose and the average therapeutic dose. The TI is also sometimes referred to as the therapeutic ratio.
The rest of this article is about IC50 I for inhibition, for downward sloping dose-response curves. All the ideas can be applied to stimulatory curves and EC50 E for effective as well. Just stand on your head when you view the figures.
The ideal situation This figure shows an ideal situation: The green symbols show measurements made with controls. The data of the experimental dose-response curve red dots extend all the way between the two control values. When fitting this curve, you need to decide how to fit the top plateau of the curve. You have three choices: Fit the data only, ignoring the Blank control values.
Average the Blank control values, and set the parameter Top to be a constant value equal to the mean of the blanks. Enter the blank values as if they were part of the dose-response curve. Simply enter a low dose, perhaps or You can't enter zero, because zero is not defined on a log scale.
The results will be very similar with any of these methods, because the data form a complete dose-response curve with a clear top plateau that is indistinguishable from the blank. I prefer the third method, as it analyzes all the data, but that is not a strong preference. Similarly, there are three ways to deal with the bottom plateau: That is the ideal situation. There is no ambiguity about what IC50 means.
A situation where IC50 can be defined in two ways This figure shows an unusual situation where the inhibition curve plateaus well above the control values NS defined by a high concentration of a standard drug.
Potency (pharmacology) - Wikipedia
This leads to alternative definitions of IC Clearly, a single value cannot summarize such a curve. You'd need at least two values, one to quantify the middle of the curve the drug's potency and one to quantify how low it gets the drug's maximum effect. The graph above shows two definitions of the IC The relative IC50 is by far the most common definition, and the adjective relative is usually omitted.
The NS values are totally ignored with this definition of IC This definition is the one upon which classical pharmacological analysis of agonist and antagonist interactions is based.
With appropriate consideration of the biological system and concentrations of interacting ligands, estimated Kd values can often be derived from the IC50 value defined this way not so for the "so-called absolute IC50" mentioned below.
This term is not entirely standard. The concept but not the term "absolute IC50" is used to quantify drugs that slow cell growth. The abbreviation GI50 is used for what we call here the absolute IC