Dose-Response Relationships - Clinical Pharmacology - Merck Manuals Professional Edition
Feb 28, Overview. Efficacy. maximum effect that a drug can produce regardless of dose. Potency. amount of a drug that is needed to produce a given. After reading this article, readers should have an understanding of the relationships between receptor potency and clinical efficacy. DATA SOURCES: Following. Jul 2, Potency is the concentration (EC50) or dose (ED50) of a drug the exam candidate to "define and explain dose-effect relationships of drugs.
Drugs that activate receptors agonists must have both great affinity and intrinsic activity: They must bind effectively to their receptors, and the drug bound to its receptor drug-receptor complex must be capable of producing an effect in the targeted area. In contrast, drugs that block receptors antagonists must bind effectively but have little or no intrinsic activity because their function is to prevent an agonist from interacting with its receptors.
Potency strength refers to the amount of drug usually expressed in milligrams needed to produce an effect, such as relief of pain or reduction of blood pressure. For instance, if 5 milligrams of drug A relieves pain as effectively as 10 milligrams of drug B, drug A is twice as potent as drug B.
Efficacy is a drug's capacity to produce an effect such as lowering blood pressure. For example, the diuretic furosemide eliminates much more salt and water through urine than does the diuretic hydrochlorothiazide. Thus, furosemide has greater efficacy than hydrochlorothiazide.
Effectiveness differs from efficacy in that it takes into account how well a drug works in real-world use. Often, a drug that is efficacious in clinical trials is not very effective in actual use. For example, a drug may have high efficacy in lowering blood pressure but may have low effectiveness because it causes so many side effects that people take it less often than they should or stop taking it entirely.
Thus, effectiveness tends to be lower than efficacy. Greater potency, efficacy, or effectiveness does not necessarily mean that one drug is preferable to another.
When judging the relative merits of drugs for a person, doctors consider many factors, such as side effects, potential toxicity, duration of effect which determines the number of doses needed each dayand cost. 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.
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.
Potency (pharmacology) - Wikipedia
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.
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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. A drug having a TI of 2 would be relatively unsafe, because doubling the dose e. If this number is much greater than one, it is a relatively safe drug. The reason this index is less commonly used is because the LD1 value, at least for human populations, is typically unknown or poorly defined, for ethical reasons!
The relationship between the dose-response relationships for producing therapeutic and toxic side effects. This topic will be covered in more depth later during the course. Examples of physiological, chemical and pharmacokinetic antagonism were discussed above. When two drugs with similar mechanisms are given together, they typically produce additive effects.
This is also referred to as summation.
Efficacy vs. Potency - Pharmacology - Medbullets Step 1
However, if the effect of two drugs exceeds the sum of their individual effects, this is referred to as potentiation or synergism. Potentiation requires that the drugs act at different receptors or effector systems. An example of potentiation would be the increase in beneficial effects noted in the treatment of AIDS by combination therapy with AZT a nucleoside analog that inhibits HIV reverse transcriptase and a protease inhibitor protease activity is important for viral replicationor the combined effects of norepinephrine and cocaine on arterial blood pressure.
An additional graphical illustration of additive and synergistic effects is shown in Figure Illustration of drug combinations producing Summation vs. Drugs A and B produce equal effects, and their effects are additive when combined.
Desensitization Receptor-mediated responses to drugs, hormones and neurotransmitters commonly desensitize with time. Following an initial response such as cellular accumulation of cAMP, Na influx, K efflux the response produced by the agonist will gradually diminish over seconds to minutes despite the continual presence of the agonist Figure The mechanism underlying desensitization varies from system to system, and is sometimes obscure.
Two mechanisms that have been documented include: Despite the constant presence of acetylcholine, the response evoked by stimulation of muscarinic receptors see Figure 5 cannot be maintained. Frishman WH, Saunders E J Clin Hypertens Pharmacologic Analysis of Drug-Receptor Interaction. The physiological significance of constitutive receptor activity.
Trends in Pharmacological Sciences 26 Inverse agonism and its therapeutic significance. Seifert R, Wenzel-Seifert K Constitutive activity of G-protein-coupled receptors: Naunyn Schmiedebergs Arch Pharmacol. Clinical Pharmacology, A conceptual approach.