Graded dose response relationship definition

Dose-Response Relationship |

graded dose response relationship definition

Source for information on Dose-Response Relationship: Encyclopedia of A graded dose-response curve plots the degree of a given response against the. The relationship between dose and drug effect can be expressed Graded - The graded dose-effect is measured in a single biologic unit (a cell, a tissue or . variation in the threshold dose required to produce a defined all-or-none effect in a. The dose–response relationship, or exposure–response relationship, describes it from a graded dose-response curve, where response is continuous (either the half maximal effective concentration, where the EC50 point is defined as the.

It is important to note the similarity between these curves and those representing the relationship between dose and effect 4. Relationship of binding to effect: The binding of the drug to its receptor initiates events that ultimately lead to a measurable biologic response. The mathematical model that describes drug concentration and receptor binding can be applied to dose drug concentration and response or effectproviding the following assumptions are met: If a drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand, it is known as an agonist.

The shortening of the muscle cells decreases the diameter of the arteriole, causing an increase in resistance to the flow of blood through the vessel. Blood pressure therefore rises to maintain the blood flow. As this brief description illustrates, an agonist may have many effects that can be measured, including actions on intracellular molecules, cells, tissues, and intact organisms.

graded dose response relationship definition

All of these actions are attributable to interaction of the drug molecule with the receptor molecule. In general, a full agonist has a strong affinity for its receptor and good efficacy 6. Antagonists are drugs that decrease the actions of another drug or endogenous ligand.

Antagonism may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist.


Antagonists, however, have no intrinsic activity and, therefore, produce no effect by themselves. Although antagonists have no intrinsic activity, they are able to bind avidly to target receptors because they possess strong affinity. Plotting the effect of the competitive antagonist characteristically causes a shift of the agonist dose—response curve to the right.

Competitive antagonists have no intrinsic activity. A drug may also act as a chemical antagonist by combining with another drug and rendering it inactive. For example, protamine ionically binds to heparin, rendering it inactive and antagonizing heparin's anticoagulant effect. An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. A classic example is the antagonism by epinephrine to histamine-induced bronchoconstriction.

Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Partial agonists have efficacies intrinsic activities greater than zero, but less than that of a full agonist. Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist.

However, a partial agonist may have an affinity that is greater than, less than, or equivalent to that of a full agonist. A unique feature of these drugs is that, under appropriate conditions, a partial agonist may act as an antagonist of a full agonist.

Consider what would happen to the Emax of an agonist in the presence of increasing concentrations of a partial agonist Figure: Effects of partial agonists. As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist. This potential of partial agonists to act both agonistically and antagonistically may be therapeutically exploited.

graded dose response relationship definition

For example, aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors. Dopaminergic pathways that were overactive would tend to be inhibited by the partial agonist, whereas pathways that were underactive may be stimulated. This might explain the ability of aripiprazole to improve many of the symptoms of schizophrenia, with a small risk of causing extrapyramidal adverse effects.

When plotted on a semi-log scale logarithm of drug concentration vs. Drugs are commonly divided into two basic categories: Agonists are drugs that bind and activate receptors.

Antagonists are drugs that bind to receptors without activating them, and consequently prevent the binding of other agonists. Differences in drug potency are evaluated by comparing EC50 or ED50 values.

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Differences in drug efficacy are evaluated by comparing differences in maximal response at high drug doses or concentrations. In contrast, full agonists produce a full or maximal response.

Dose Response Curve

Two fundamental properties of agonists are affinity and efficacy. Affinity can be defined as the tenacity with which a drug binds to its receptor. In statistical terms, it can be defined as the probability that a drug molecule will bind to an available receptor at any given instant in time. Efficacy is an inherent property of an agonist that determines its ability to produce its biological effect. By definition, it is a property of the drug, not the receptor or tissue. Affinity gets the drug bound to the receptor, and efficacy determines what happens once the drug is bound.

The term potency is used as a comparative term for distinguishing which agonist has a higher affinity for a given receptor Figure 2. Schematic illustration of the dose-response curves for a series of agonists A, B, C and D that have the same efficacy, but differ in terms of their potency.

Agonists can also differ in terms of their efficacy, or maximum response. Figure 4 shows a plot of four agonists that differ in terms of their relative efficacy. Drug A is the most efficacious, and Drug D the least. Drugs that bind to a receptor, but produce less than maximal activation e.

graded dose response relationship definition

Dose-response relationships for four agonists that vary in efficacy. Each drug has essentially the same EC50 value equi-potentbut differ in terms of the maximum response they can produce at high concentrations that saturate all available receptor sites. Clinical Examples of Partial Agonists Clinically used examples of partial agonists include: Schizophrenia is a condition associated with both excess dopamine activity in one area of the brain resulting in hallucinations and delusionsas well as a co-existing reduced dopamine activity in another area causing cognitive impairment.

Aripiprazole is thought to produce beneficial effects in schizophrenia by exerting agonist effects in areas of dopamine deficit, while exerting sufficient antagonist effects in areas of dopamine hyperactivity. The presence of ISA results in a neutral effect on heart rate and cardiac output when the sympathetic nervous system is not activated e.

They may be an appropriate choice for patients who require a beta blocker e. They are generally considered undesirable for use in patients who have previously had an myocardial infarction, since this may interfere with their otherwise anti-ischemic properties on the heart. Signal Transduction Mechanisms for Agonists Once an agonist has bound to its receptor, its effects are transduced into a cellular response by one of several different mechanisms.

A few of the most common mechanisms include: Examples of these mechanisms are shown below. Direct activation of an ion channel The drug receptor is structurally attached to an ion channel. 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. 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. 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.

Dose–response relationship

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.

graded dose response relationship definition

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.

Dose-Response Relationships - Clinical Pharmacology - MSD Manual Professional Edition

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.

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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.