Drug–Receptor Interactions and Pharmacodynamics

•  Overview 

Most drugs exert their effects, both beneficial and harmful, by interacting with receptors—that is, specialized target macromolecules—present on the cell surface or intracellularly. Receptors bind drugs and initiate events leading to alterations in biochemical and/or biophysical activity of a cell, and consequently, the function of an organ 

Figure  The recognition of a drug by a receptor triggers a biologic response.

Drugs may interact with receptors in many different ways. Drugs may bind to enzymes (for example, inhibition of dihydrofolate reductase by trimethoprim, nucleic acids (for example, blockade of transcription by dactinomycin ) or membrane receptors (for example, alteration of membrane permeability by pilocarpine, ) .In each case, the formation of the drug–receptor complex leads to a biologic response. Most receptors are named to indicate the type of drug/chemical that interacts best with it; for example, the receptor for histamine is called a histamine receptor. Cells may have tens of thousands of receptors for certain ligands (drugs). Cells may also have different types of receptors, each of which is specific for a particular ligand. On the heart, for example, there are β receptors for norepinephrine, and muscarinic receptors for acetylcholine. These receptors dynamically interact to control vital functions of the heart. The magnitude of the response is proportional to the number of drug–receptor complexes

This concept is closely related to the formation of complexes between enzyme and substrate,1 or antigen and antibody; these interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given ligand. However, the receptor not only has the ability to recognize a ligand, but can also couple or transduce this binding into a response by causing a conformational change or a biochemical effect. Although much of this chapter will be centered on the interaction of drugs with specific receptors, it is important to be aware that not all drugs exert their effects by interacting with a receptor; for example, antacids chemically neutralize excess gastric acid, reducing the symptoms of “heartburn.” This chapter introduces the study of pharmacodynamics—the influence of drug concentrations on the magnitude of the response. It deals with the interaction of drugs with receptors, the molecular consequences of these interactions, and their effects in the patient. A fundamental principle of pharmacodynamics is that drugs only modify underlying biochemical and physiological processes; they do not create effects de novo. 

II. Chemistry of Receptors and Ligands 

Interaction of receptors with ligands involves the formation of chemical bonds, most commonly electrostatic and hydrogen bonds, as well as weak interactions involving van der Waals forces. These bonds are important in determining the selectivity of receptors, because the strength of these noncovalent bonds is related inversely to the distance between the interacting atoms. Therefore, the successful binding of a drug requires an exact fit of the ligand atoms with the complementary receptor

atoms. The bonds are usually reversible, except for a handful of drugs (for example, the nonselective α-receptor blocker phenoxybenzamine, and acetylcholinesterase inhibitors in the organophosphate class) that covalently bond to their targets. The size, shape, and charge distribution of the drug molecule determines which of the myriad binding sites in the cells and tissues of the patient can interact with the ligand. The metaphor of the “lock and key” is a useful concept for understanding the interaction of receptors with their ligands. The precise fit required of the ligand echoes the characteristics of the “key,” whereas the opening of the “lock” reflects the activation of the receptor. The interaction of the ligand with its receptor thus exhibits a high degree of specificity. The induced-fit model has largely replaced the lock-and-key concept as the preferred model describing the interaction of a receptor and a ligand. In the presence of a ligand, the receptor undergoes a conformational change to bind the ligand. The change in conformation of the receptor caused by binding of the agonist activates the receptor, which leads to the pharmacologic effect. This model suggests that the receptor is flexible, not rigid as implied by the lock-and-key model

Figure : Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.

III. Major Receptor Families

Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses. 

A. Ligand-gated ion channels The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes

B. G protein–coupled receptors A second family of receptors consists of G protein–coupled receptors.

C. Enzyme-linked receptors A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function

D. Intracellular receptors The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor 

 IV. Some Characteristics of Receptors

A. Spare receptors
B. Desensitization of receptors 

C. Importance of the receptor concept

V .Dose–Response Relationships 

1. Potency
2. Efficacy [intrinsic activity]
3. Drug–receptor binding
4. Relationship of binding to effect
5. Agonists
6. Antagonists
7. Functional antagonism
8. Partial agonists

VI. Quantal Dose–Response Relationships Another important dose–response relationship is that of the influence of the magnitude of the dose on the proportion of a population that responds. These responses are known as quantal responses, because, for any individual, the effect either occurs or it does not. Even graded responses can be considered to be quantal if a predetermined level of the graded response is designated as the point at which a response occurs or not. For example, a quantal dose–response relationship can be determined in a population for the antihypertensive drug atenolol. A positive response is defined as at least a 5 mm Hg fall in diastolic blood pressure. Quantal dose–response curves are useful for determining doses to which most of the population responds

A. Therapeutic index

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals: where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population. The therapeutic index is a measure of a drug's safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic. 

B. Determination of therapeutic index

The therapeutic index is determined by measuring the frequency of desired response, and toxic response, at various doses of drug. By convention, the doses that produce the therapeutic effect and the toxic effect in fifty percent of the population are employed; these are known as the ED50 and TD50, respectively. In humans, the therapeutic index of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses. Although some drugs have narrow therapeutic indices, they are routinely used to treat certain diseases. Several lethal diseases, such as Hodgkin's lymphoma, are treated with narrow therapeutic index drugs; however, treatment of a simple headache, for example, with a narrow therapeutic index drug would be unacceptable

Figure above  shows the responses to warfarin, an oral anti-coagulant with a narrow therapeutic index, and penicillin, an antimicrobial drug with a large therapeutic index.

1. Warfarin (example of a drug with a small therapeutic index): As the dose of warfarin is increased, a greater fraction of the patients respond (for this drug, the desired response is a two-fold increase in prothrombin time) until eventually, all patients respond. (see Figure A).

 However, at higher doses of warfarin, a toxic response occurs, namely a high degree of anticoagulation that results in hemorrhage.

(Note: that when the therapeutic index is low, it is possible to have a range of concentrations where the effective and toxic responses overlap. That is, some patients hemorrhage, whereas others achieve the desired two-fold prolongation of prothrombin time. Variation in patient response is, therefore, most likely to occur with a drug showing a narrow therapeutic index, because the effective and toxic concentrations are similar. Agents with a low therapeutic index—that is, drugs for which dose is critically important —are those drugs for which bioavailability critically alters the therapeutic effects .

 2. Penicillin (example of a drug with a large therapeutic index): For drugs such as penicillin (see Figure B),

 it is safe and common to give doses in excess (often about ten-fold excess) of that which is minimally required to achieve a desired response. In this case, bioavailability does not critically alter the therapeutic effects.

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