basic_principles_of_pharm [TUSOM | Pharmwiki]
IC50 is an operational parameter defined as the concentration of inhibitor .. the difference between IC50 and Ki,app, and the drawbacks surrounding IC Learn quiz drug receptor interactions with free interactive flashcards. Choose from different sets of quiz drug receptor interactions flashcards on Quizlet. EC - Effective Concentration (e.g. EC the drug concentration producing 50% Pharmacodynamics - The study of the relationship between.
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.
50% of what? How exactly are IC50 and EC50 defined?
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. This leads to alternative definitions of IC Clearly, a single value cannot summarize such a curve.
What is required is an accurate determination of the Ki value, an intrinsic, thermo-dynamic quantity that is independent of the substrate ligand but depends on the enzyme target and inhibitor.
Thus, comparisons can be more readily made among different laboratories to characterize the inhibitors. While these more time-consuming assays are usually done with the most promising candidates, accurate, initial estimates of Ki values for more of the candidates would be beneficial. A much discussed problem in the literature 1—8 is converting IC50 to Ki values because even the simplest types of inhibitory mechanisms e.
To help address this problem, our web-server tool calculates Ki values from IC50 values using equations for enzyme-substrate and target-ligand interactions by different inhibitory mechanisms http: Additional calculations are performed for tightly bound inhibitors of enzyme-substrate reactions in which free, rather than total, concentrations of the molecular species are calculated for nonclassic Michaelis—Menten kinetics.
Similar calculations can be performed for target molecule-ligand systems. User-defined input values include total concentrations of the enzyme or target molecule and substrate or ligandthe Km of the enzyme-substrate or the Kd of the target-ligand reaction and the IC50 value.
The outputs include tabulations of the Ki values under different kinetic schemes, extensive tabulations of the results, summary histograms and the corresponding equations.
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. 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.
IC50 - Wikipedia
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. 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.