Dose-Response Relationships - Clinical Pharmacology - MSD Manual Professional Edition
drug to be potent (i.e. active in small doses) but have a low efficacy. ffinity can be The test compound competes with the radioligand for the receptor's is non- competitive (K = IC50), but the relationship becomes more complicated (Cheng-. Dose-Response Relationships and Clinical Pharmacology - Learn about from the Biologic variation (variation in magnitude of response among test subjects in the same Drug Y is more potent than drug Z, but its maximal efficacy is lower. 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 initiate a response at the molecular, cellular, tissue or system level. In other.
Does potency predict clinical efficacy? Illustration through an antihistamine model.
Many drug receptors can transduce biological signals at very low concentrations i. For example, calculations from studies of atropine binding to the intestinal ileum suggest that only 0. Receptor Subtypes Drug receptors can be classified into several major subtypes including: Stimulation of membrane receptors typically results in the altered activity of membrane-associated enzymes or channels via activation of specific G-proteins located on the intracellular membrane surface.
An exception to this rule are receptors with tyrosine kinase activity see below. The Chemical Basis for Drug-Receptor Interactions Drugs can interact with receptors through a variety of chemical interactions including: Electrostatic interactions hydrogen bonds, Van der Waals forces - the most common mechanism. Hydrophobic interactions important for lipid soluble drugs.
The Dose Response Relationship The fraction of receptors occupied by a drug is a function of the drug concentration.
As the drug concentration is increased, a progressively higher fraction of available receptors will become occupied by drug until all available receptors become bound. An illustration of the relationship between drug concentration and receptor occupancy by drug is shown in Figure 2.
When plotted on a linear scale left panela dose-response relationship is hyperbolic, and can typically be well described by a Langmuir binding isotherm.
At high concentrations the response reaches a maximum due to saturation of available receptors by drug. 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.
Differences in drug efficacy are evaluated by comparing differences in maximal response at high drug doses or concentrations.
Potency (pharmacology) - Wikipedia
In contrast, full agonists produce a full or maximal response. 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.
- BASIC PRINCIPLES OF PHARMACOLOGY
- Efficacy vs. Potency
- Potency (pharmacology)
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.
Efficacy and Potency
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. 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. 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. The agonist, the ligand, drug or hormone that binds to the receptor and initiates the response is usually abbreviated A or D. Below a certain concentration of agonist [A]E is too low to measure but at higher concentrations it becomes appreciable and rises with increasing agonist concentration [A] until at sufficiently high concentrations it can no longer be increased by raising [A] and asymptotes to a maximum Emax.
The Emax is the maximum possible effect for the agonist. The term "potency" refers to the [A]50 value. Higher potency does not necessarily mean more side effects. The pharmacophore is the part of the drug molecule - the atoms and groups - that bind to the receptor; the "auxophore" are the parts of the molecule that are not directly involved in binding, but may rather interfere with binding, be essential for the arrangement of pharmacophoric elements, or may be irrelevant.
Update on terms and symbols in quantitative pharmacology".