Agonists and antagonists Drugs that interact with receptors can be classified as either agonists or antagonists. Agonists have an affinity for a receptor, and, once bound to it, activate or enhance cellular activity, producing a specific action or response. Many ligands, and some drugs, regulate the function of receptor macromolecules as agonists, meaning they activate the receptor as they bind to it. Antagonists, in contrast, can bind to a receptor, but do not trigger a sequence of biochemical events that ultimately leads to a change in function. Drugs that bind to receptors and do not cause a response (agonists) are also called receptor blockers because they bind to or occupy a receptor, thus interfering with an agonist’s ability to bond, and preventing action. While antagonists bind to receptors, they do not activate them. Instead, their effects result because they prevent other drugs or regulatory molecules produced by the body (agonists) from binding to and activating receptors. Many useful drugs are pharmacologic antagonists, which block, rather than activate, biological actions, therefore blocking drug action or reducing the effects of certain drugs on the body. In some cases, a chemical antagonist may not even involve a receptor; instead, one drug brings about effects in another drug. Agonists can stimulate a receptor in such a way that its cellular signaling is activated. However, agonists differ in their degree of ability to activate a receptor. As a result, agonists can be further categorized as full or partial Affinity and intrinsic activity Two factors that determine the effect of a drug on physiologic processes are affinity and intrinsic activity. Affinity is a measure of tightness with which a drug binds to the receptor. Intrinsic activity is a measure of the ability of a drug, once it occupies or binds to the receptor, to generate an effect. Agonists have both affinity and intrinsic activity. Antagonists, on the other hand, only have affinity for the receptor, allowing them to bind but not produce an effect. Both affinity and intrinsic activity determine which particular effect of a drug will be observed. For example, consider a drug that can produce actions at two receptors: At each receptor, the ligand, or macromolecule, has a different affinity as well as pharmacologic effect. This means the drug could have either beneficial or toxic effects, depending on the receptor occupied. The observed effect of the drug is determined by the concentration of the drug and its affinity for the receptor, as well as its degree of receptor occupancy. The sensitivity of a Dose-response curves A basic principle of pharmacology is that a relationship exists between the concentration of a drug at its target site (site of action) and its beneficial or toxic action. The dependence of pharmacodynamic effects upon drug concentration establishes the relationship between pharmacokinetics and pharmacodynamics: It is the action of the body upon the drug (pharmacokinetics) that determines its concentration at the site of action. The relationship between dosage and effect can be very complicated. At its most simple level, drug effects increase in direct proportion to dosage. At greater doses, however,
agonists. Partial agonists bring about a lower response to complete receptor occupancy than do full agonists. Full agonists produce the maximum response once receptors are occupied and activated. The drug’s action is determined by whether it is the agonist or antagonist that occupies the majority of receptors. Antagonists must compete with agonists for receptor sites. If an antagonist and agonist are competing for the same limited number of receptors, the drug that binds to the receptor in the highest concentration will be determined by two factors: ● The affinities of the agonist and antagonist for the receptor. ● Their relative concentrations. The effects or clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors. Depending on the concentration of agonist, larger concentrations of a competitive antagonist increasingly inhibit the agonist response, with high antagonist concentrations preventing response completely. The opposite is also true: High concentrations of agonist can overpower the effect of a specific concentration of the antagonist. The full spectrum of drug activity can range from a full agonist to a full inverse agonist. Full agonist → Partial agonist → Neutral agonist → Partial inverse agonist → Full inverse agonist cell, tissue or organism to a particular concentration of drug depends on both factors: The affinity of the receptor for binding the drug as well as the degree of sparseness, that is, the total number of receptors occupied compared to the number required for a maximum biological response. A cell with four receptors and four effectors (and no spares) will not limit the maximal effects of the drug. If drug concentration is such that only two of the four receptors are occupied or activated, it may produce half of the maximum response. If 40 receptors exist and only two are occupied, the great majority of receptors are spare. The maximum observed effect is a product of all receptors being occupied. This explains the powerful nature of some drugs, as a drug with very high affinity will achieve a large degree of receptor saturation at very low concentrations. Therefore, the ability of a drug to produce a physiologic effect is dependent on: ● Receptor occupancy. ● The propensity of the drug to activate the receptor. the amount of effect diminishes, until at some point no further effect is achieved (called the “ceiling effect”). Drug effect reaches a plateau or maximum because there are a finite number of receptors. Note that at low concentrations, the effect of dosage changes rapidly, while at high concentrations, the effect of dosage changes more slowly. Drug action terminates for a number of reasons. In some cases, drug effects last only as long as the drug occupies the receptor. More typically, the action continues for some period of time after the drug leaves the receptor.
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