The definition of drug, in the most general sense, is that a drug may be defined as any substance that brings about a change in biologic function through its chemical actions.

The Foundational Section

Generally, four primary factors affect drug-receptor interactions, including 1.drug’s affinity to the according receptor (with respect to Kd);2.the efficiency of the occupancy-response (determined by initial conformational change in the receptor and biochemical events that transduce receptor occupancy into cellular response);3.degree of spareness (the total number of receptors present compared with the number actually needed to elicit a maximal biologic response);and 4.total number of receptors (determining maximum effect, in the absence of point 3).

The Nature of Drugs

In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions.

In most cases, the drug molecule interacts as an agonist or antagonist with a specific molecule (receptor) in the biologic system that plays a regulatory role. However, in a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Also, physiologic antagonism where, for instance, several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin which act on quite distinct receptor-effector system. Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus famously stated that “the dose makes the poison”, meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, in contrast to inorganic poisons such as lead and arsenic. However, in some diseases (e.g., APL), poisons can be used to treat diseases, for instance, arsenic for acute promyelocytic leukemia.

Drug size, acid-base property, shape or stereoisomerism, and drug-receptor bonds all decide the characteristics of a drug. Most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body (e.g., from the site of administration to the site of action).

Drug acid-base property and human body pH in different compartments impact the way these drugs are handled by the body (altering the degree of ionization of a drug). The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds. Optimally, the drug’s shape is complementary to that of the receptor site in the same way that a key is complementary to a lock, which makes the effects of different chirality form of a same drug different.

Drug-receptor bonds include three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. An example of covalent drug-receptor bond can be found here http://forum.tomhsiung.com/pharmacogenetics-and-pharmacology/398-an-example-of-covalent-drug-receptor-bonds.html.

Electrostatic bonding is much more common than covalent bonding in drug–receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Nevertheless, electrostatic bonds are weaker than covalent bounds.

Hydrophobic bonds are usually quite weak and are probably important in the interaction of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “prockets”. The significance of the type of drug-receptor bonds is that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur (we call it the conformation change). Thus, in general, if we wished to design a highly selective short-acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds.


Pharmacodynamic Principles and Drug-Receptor Binding

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.

Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule and the binding brings about the effect indirectly.

Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into full agonist and partial agonists. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists.

Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blcoks some of the receptor sites (see below). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonists.

Antagonist drugs bind to a receptor but do not activate receptor effectively, meanwhile antagonists compete with and prevent binding by other ligands (other drugs or endogenous regulatory molecules). They stabilize the receptor in its inactive state or some state other than activated state. Of note antagonist-receptor bind can be reversible or irreversible. However, face to antagonist, receptor activated effect could still be achieved by increased the dosage of the agonist.

Antagonists are divided into two classes depending on if or not they reversibly compete with agonists for binding to receptors. (see below for detail)

For competitive antagonists, the degree of inhibition produced by them depends on the concentration of antagonist. And, clinical response to a competitive antagonist also depends on the concentration of agonist that is competing for binding to receptors.

Irreversible antagonists bind to the receptor and this binding is irreversible or nearly irreversible. After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response. Therapeutically, irreversible antagonists present distinct advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses, thus the duration of action is relatively independent of its own rate of elimination (pharmacokinetic parameter).

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 inhibitioin is not overcome by increasing the dose of agonist. The drugs of this type modify receptor activity without blocking agonist binding.

Another form of drug-receptor interaction can be termed as ‘agonist that inhibit their binding molecules’. the acetylcholinesterase inhibitors are the classic example of these drugs. These drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist.

At present, there is another theory that can explain the drug-receptor binding we have talked about above.

As indicated, the receptor is postulated to exist in the inactive, nonfunctional form (Ri) and in the activated form (Ra). Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the Ra form some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence of agonist, is termed constitutive activity.

In this theory agonists are those drugs that have a much higher affinity for Ra configuration and stabilize it, so that a large percentage of the total pool resides in the Ra-D fraction and a large effect is produced. Again, based on the maximal pharmacologic response that occurs when all receptors are occupied, full agonists are drugs that shift of almost all of  the receptor pool to the Ra-D pool. Other drugs, called partial agonists, bind to the same receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration.

In the figure at left side, partial agonist do not stabilize the Ra configuration as fully as full agonists, so that a significant fraction of receptors exists in the Ri-D pool (in the setting of all receptors have been occupied). Such drugs are said to have low intrinsic efficacy. Thus, these drugs may act either as an agonist (if no full agonist is present) or as an antagonist (if a full agonist is present). Note that intrinsic efficacy is independent of affinity for the receptor. That is the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonist (if a full agonist is present).

In the same model, conventional antagonist action can be explained as fixing the fractions of drug-bound Ri and Ra in the same relative amounts as in the absence of any drug. In this situation, no change will be observed, so the drug will appear to be without effect. However, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect. Such blocking action can be termed neutral antagonism.

If a drug has much stronger affinity for the Ri than Ra state and stabilizes a large fraction in the Ri-D pool, the drug would reduce any constitutive activity, thus resulting in effects that are the opposite of the effects produced by conventional agonists at that receptor. The drug inducing this phenomenon is termed inverse agonists.

Other Mechanisms of Drug Antagonism

The antagonism we have discussed above firstly belongs to chemical antagonism, in that, a antagonist acts simply by ionic binding the receptor and results in the receptor unavailable for interactions with other drugs.

Another type of antagonism is physiologic antagonism between endogenous regulatory pathways mediated by different receptors. For example, several catabolic action of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector system, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of a glucocorticoid hormone, whether the latter is elevated by endogenous synthesis (e.g., a tumor of the adrenal cortex) or as a result of glucocorticoid therapy.

In general, use of a drug as physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist (chemical antagonist).


Characteristics of Drug-Receptor Binding

Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce.

Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether-and with what affinity-it will bind to a particular receptor among vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.

Receptors mediates the actions of pharmacologic agonists and antagonists. Some drugs and many natural ligands regulate the function of receptor macromolecules as agonists; this means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic function, whereas others selectively promote one receptor function more than another. Antagonists bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. The effect of so-called “pure” antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions. Others, in addition to prevent agonist binding, suppress the basal signaling (“constitutive”) activity of receptors.

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.

In addition, many receptor-effector systems incorporate desensitization mechanisms for prevent excessive activation when agonist molecules continue to be present for long periods.

Inert Binding Sites

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 nonregulatory 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. However, such binding is clinical significant since it affects the distribution of the drug within the body, which belongs to pharmacokinetics and beyond the scope of this thread.


Relation Between Drug Concentration and Response

The relation between dose of a drug and the clinically observed response may be complex (actually it is true). The below relation between drug concentration and drug response is in carefully controlled systems in vitro.

Concentration-Effect Curves & Receptor Binding of Agonists

Responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. In ideal or in vitro systems, the relation between drug concentration and effect is described by a hyperbolic curve. The formula for this curve is as follow.

E = ( Emax × C ) ÷ ( C + EC50 )

where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produce 50% of maximal effect. Similarly, the relation between drug-receptor binding and drug concentration could be described by the hyperbolic curve too.

B = ( Bmax × C ) ÷ (C + Kd )

where Bmax indicates the total concentration of receptor sites, and Kd represents the concentration of free drug at which half-maximal binding is observed. This constant characterizes the receptor’s affinity for binding the drug in reciprocal fashion: If the Kd is low, binding affinity is high, and vice versa.

The EC50 and Kd may be identical, but need not be. Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa), which transforms the hyperbolic curve as described above into a sigmoid curve with a linear midportion.

PS: attention must be paid that not only the affinity of the receptor for binding the agonist but also the degree of spareness (see below) – the total number of receptors present compared with the number actually needed to elicit a maximal biologic response determine the sensitivity of a cell or tissue to a particular concentration of agonist.

Receptor-Effector Coupling & Spare Receptors

When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response. The transduction process that links drug occupancy of receptors and pharmacologic response is often termed coupling.

Coupling efficiency is relative to if the agonist is full or partial agonist, which determine the conformational change in the receptor; also, coupling efficiency is determined by the biochemical events that transduce receptor occupancy into cellular response. Sometimes the biologic effect of the drug is linearly related to the number of receptors bound. In other cases, the biologic response is a more complex function of drug binding to receptors. This is often true for receptors linked to enzymatic signal transduction cascades.

Many factors can contribute to nonlinear occupancy-response coupling, and often these factors are only partially understood. The concept of “spare” receptors, regardless of the precise biochemical mechanism involved, can help us to think about these effects. Receptors are said to be “spare” for a given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does result in occupancy of the full complement of available receptors. The figure at left show drug concentration-response curve and the phenomenon of spare receptors.

The mechanism of spare receptor are described below. In example of beta adrenoceptor, receptor activation promotes binding of guanosine triphosphate to an intermediate signaling protein and activation of the signaling intermediate may greatly outlast the agonist-receptor interaction. In such case, the “spareness” of receptors is temporal. Maximal response can be elicited by activation of relatively few receptors because the response initiated by an individual ligand-receptor binding event persists longer than the binding event itself.

In other cases, in which the biochemical mechanism is not understood, we imagine that the receptors might be spare in number. If the concentration or amount of cellular components other than the receptors limits the coupling of receptor occupancy to response, then a maximal response can occur without occupancy of all receptors.

Competitive & irreversible antagonists

The concentration (C’) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (dose ratio) is related to the dissociation constant (Ki) of the antagonist by the Schild equation:

C’ / C = 1 + [I] ÷ Ki