The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamics. These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes.
Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, e.g., a patient with impaired renal function. The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics.
Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in what is often a complex sequence of steps:
· Drug (D) + receptor-effector (R) → drug-receptor-effector complex → effect
· D + R → drug-receptor complex → effector molecule → effect
· D + R → D-R complex → activation of coupling molecule → effector molecule → effect
· Inhibition of metabolism of endogenous activator → increased activator action on an effector molecule → increased effect
Note that the final change in function is accomplished by an effector mechanism. The effector may be part of the receptor molecule or may be a separate molecule. A very large number of receptors communicate with their effectors through coupling molecules
Agonist and Antagonist drugs
Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect. Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level.
Pharmacologic antagonist drugs, by binding to a receptor, compete with and prevent binding by other molecules. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylchol ine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body, but their action can be overcome by increasing the dosage of agonist.
Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allosterically and may enhance or inhibit the action of the agonist molecule. Allosteric inhibition is not overcome by increasing the dose of agonist.
Duration of Drug Action
Termination of drug action is a result of one of several processes. In some cases, the effect lasts only as long as the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form.
In the case of drugs that bind covalently to the receptor site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized, as described previously for aspirin.
In addition, many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods.
Receptors and Inert Binding Sites
To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug molecules) to bind; and second, it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc.) is altered. The selectivity characteristic is required to avoid constant activation of the receptor by promiscuous binding of many different ligands. The ability to change function is clearly necessary if the ligand is to cause a pharmacologic effect.
The body contains a vast array of molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a non-regulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such binding is not completely without significance, however, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance