Dose response data was collected during the preclinical testing of four drugs for the treatment of acute heart failure. Which drug studied was the most efficacious. What is Pharmacodynamics Drug response curve EC50 Potency Efficacy Refrences; 4. Pharmacodynacmics describes the action. Dose-Response Relationships and Clinical Pharmacology - Learn about from the and is thus more potent than drug Y or Z. Drugs X and Z have equal efficacy.
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Unsourced or poorly sourced material may be challenged and removed. March Learn how and when to remove this template message In the field of pharmacologypotency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
The potency depends on both the affinity and efficacy. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level. In other words, efficacy refers to how well an action is took after the drug is bound to a receptor. In pharmacology, a high efficacy usually means that a drug has worked since the drug caused the receptor to metabolize a certain compound extremely well.
Therefore, it makes sense that a drug's effectiveness, potency, is affected by how well the drug can bind to a receptor, affinity, and how it is able to cause a reaction in the receptor when bound, efficacy.
The response is equal to the effect, or Eand depends on both the drug binding and the drug-bound receptor then producing a response; thus, potency depends on both affinity and efficacy. 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.How to plot a dose response curve and measure EC50
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. 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.
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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. 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.
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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.
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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.
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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.