Drug Binding

At the molecular level, a number of factors contribute to the interaction between drug and receptor and control the strength, duration, and type of the drug-receptor interaction. Collectively these factors dictate the strength with which the drug forms a complex with its receptor, also known as the affinity:

Size and shape of the drug molecule

Types, number, and spatial arrangement of drug binding sites (stereochemistry)

Intermolecular forces between drug and binding sites

Van der Waals forces = weak bonds and transient reversible effects

Hydrogen bonds = intermediate bonds and transient reversible effects

Covalent bonds = strong bonds and long-lasting or irreversible effects

It is important to recognize that, in most cases, binding of drug to target molecules involves weaker bonds. Accordingly, the drug-receptor complex is not static, but rather there is continuous association and dissociation of the drug with the receptor as long as drug is present. A measure of the relative ease with which the association and dissociation reactions occur is the equilibrium dissociation constant (K_D). Each drug-receptor combination will have a characteristic K_D value. Drugs with high affinity for a given receptor display a small value for K_D, and vice versa. In Figure 1-1, A and B, Drug A has a higher affinity for the receptor than Drug B. K_D also represents the concentration of drug needed to bind 50% of the total receptor population. These concepts are important in the study of basic pharmacologic data regarding different compounds with affinity for the same receptor. In general, drugs with lower K_D values will require lower concentrations to achieve sufficient receptor occupancy to exert an effect.

Selectivity of Drug Responses

Another important and desirable facet of pharmacologic responses is selectivity of drug action, determined by drug molecules exhibiting preferential affinity for receptors, as follows:

The cell will respond only to the spectrum of drugs that exhibit affinity for the receptors expressed by the cell.

The greater the extent to which a drug molecule exhibits high affinity for only one receptor, the more selective will be the drug’s actions, with lower potential for side effects.

The higher the affinity and efficacy of a given drug, the smaller the amount of drug necessary to activate a critical mass of drug receptors to effect a tissue response, and the lower the potential for nonselective actions.

It is important to note that selectivity of drug action is a key concept. Few drugs are entirely specific for one receptor. Rather, drugs exhibit selectivity toward different receptors based on their relative affinities. Thus, selectivity is also relative. As the concentration of a drug increases, the drug will combine with receptors for which it has lower affinity and may generate off-target effects.

Clinical Connection: β-Adrenergic receptor antagonists are effective drugs for a number of cardiovascular disorders. Some β-adrenergic receptor antagonists are selective for β₁-adrenergic receptors to limit the potential for bronchoconstriction caused by blocking β₂-adrenergic receptors. However, even β₁-selective antagonists must be used cautiously in asthmatic patients, particularly at higher doses, to avoid further impairment of airway function in these patients.

Tissue Distribution of Receptors

Only those tissues possessing receptors will respond to the drug.

The more restricted the distribution of drug receptor, the more selective will be the effects of drugs that interact with that receptor.

Clinical Connection: Knowledge of receptor subtypes and their regional distribution can assist in drug selection. A useful example is the use of α-adrenergic receptor antagonists for the treatment of urinary retention secondary to prostatic hypertrophy. Nonselective α-adrenergic antagonists are not routinely used to treat urinary retention in men with prostatic hypertrophy, because although they block α receptors in the prostate and improve urine flow, they also block α receptors in blood vessels and cause hypotension. The prostate expresses primarily α_1B-adrenergic receptors, whereas blood vessels express other subtypes. Consequently, drugs such as tamsulosin that are selective for the α_1B subtype expressed primarily in the prostate are much more useful in the treatment of prostatic hypertrophy.

Activation of the Molecular Target

The relationship between the drug-receptor binding event and the ultimate biologic effect is complex. Quite often in experimental settings, the K_D (concentration causing 50% receptor occupancy) does not correspond to a 50% maximal response from the test tissue or organism. In fact, in many cases half-maximal tissue responses are obtained at drug concentrations below the K_D, suggesting that amplification of drug response occurs. Amplification of drug responses is discussed in a later section. This observation suggests that other factors, in addition to affinity and receptor occupancy, determine the strength of response. Accordingly, an additional modifier termed intrinsic activity was proposed. Intrinsic activity indicates the ability of receptor-bound drug to activate the receptor and initiate downstream events, leading to an effect. Drugs are categorized based on their intrinsic activity at a given receptor:

Agonists (sometimes called full agonists) produce maximum activation of the receptor and elicit a maximum response from the tissue. They are assigned an intrinsic activity of 1.

Antagonists bind but produce no activation of the receptor and therefore block responses from the tissue. They are assigned an intrinsic activity of 0.

Partial agonists exhibit intrinsic activity between 0 and 1. Partial agonists produce weaker activation of the receptor than full agonists or the endogenous ligand. Partial agonists produce only partial activation of the receptor and its downstream signaling events. The clinical effect of a partial agonist will depend on its intrinsic activity and the concentration of the endogenous ligand. If concentrations of the endogenous ligand are really low, then a partial agonist will increase receptor activation, functioning as a weak agonist. In contrast, if concentrations of endogenous ligand are high, the partial agonist will compete for receptors and bind to a certain proportion of receptors previously bound by endogenous ligand. Because the partial agonist produces weaker activation of the receptor than endogenous ligand, the net effect will be less cumulative receptor activation. This will produce inhibition of the response mediated by the endogenous ligand, and the partial agonist will act as a weak antagonist.

Inverse agonists inhibit rather than activate the receptor. This phenomenon is evident with receptors that exhibit baseline (ongoing or constitutive) activity in the absence of agonist binding. In these cases, binding of the inverse agonist reduces the baseline activity of the receptor, which in turn elicits an effect opposite that of binding of the agonist. Inverse agonists and antagonists will elicit similar effects because both types of drugs will reverse the effects of endogenous ligands. Many clinically used antagonists may in fact be inverse agonists. Inverse agonists may assume particular clinical importance in disease states in which constitutive activity of receptors plays an important role. Increasing evidence suggests that a number of diseases are a result of gain of function mutations at the receptor that result in constitutive activity of the receptor in the absence of agonist.

Clinical Connection: Drugs that act as inverse agonists may have important clinical applications for diseases in which receptors are activated in the absence of endogenous agonist. One example is in cancer chemotherapy. In a number of human cancers, mutations of the epidermal growth factor receptor cause the receptor to be active in the absence of epidermal growth factor. In this setting, a traditional antagonist would be of no benefit. However, drugs that act as inverse agonists at the epidermal growth factor would suppress receptor activation and reduce the growth signaling via this pathway. Epidermal growth factor inverse agonists are being studied as cancer chemotherapy drugs.

Thus, the ultimate action of a drug will depend on both its affinity and its intrinsic activity. It is important to remember that affinity and intrinsic activity are distinct properties. A weak partial agonist, which by definition activates a receptor only minimally, may have very high affinity for a receptor. In this case the drug will be able to effectively compete for the receptor and will usually out-compete the endogenous agonist for receptor occupancy and inhibit the endogenous response.

Graded Dose-Response Curves

Measure an effect that is continuous such that, in theory, any value is possible in a given range (0% through 100%).

Have a sigmoidal shape similar to the drug receptor occupancy curves shown in Figure 1-2, because the biologic response to a drug is determined by the interaction of a drug with a receptor or molecular target.

Exhibit a dose beyond which no further response is achieved (maximal effect; E_max). E_max is a measure of the pharmacologic efficacy of the drug.

Show the dose that produces 50% of the E_max (ED₅₀).

ED₅₀ is an index of the potency of the drug.

Agonists with higher potency will have lower ED₅₀ values.

Figure 1-2 A, Graded dose-response curve. B, Quantal dose-response curve.

The ED₅₀ and E_max are useful parameters to assess drugs. In Figure 1-2, A, Drug A is more potent than Drug B or Drug C, whereas Drugs B and C have equal potency. Potency is sometimes used incorrectly as a measure of therapeutic effectiveness. In fact, in most cases potency is secondary to E_max in drug selection. However, in situations in which the absorption of drug is very poor, such that only small quantities of the drug reach the target, potency can be a critical consideration. Drugs with higher E_max values have higher pharmacologic efficacy.

In Figure 1-2, A, Drug B has the greatest efficacy, followed by Drug C, whereas Drug A, despite being the most potent, has the least efficacy. Drug C is equipotent with Drug B but has less efficacy. Thus, potency and efficacy can vary independently. It is important not to confuse the pharmacologic usage of efficacy with the more general usage. Pharmacologic efficacy is a measure of the strength of effect produced by the maximum dose of drug. By definition, antagonists do not activate their receptors after binding and therefore have an intrinsic activity and efficacy of 0. Nevertheless, an antagonist may be very clinically “efficacious” or beneficial because it blocks activation of the receptor by endogenous agonist.

These variables can be useful in determining how much of a drug to administer. For example, knowledge of the ED₅₀ concentration for blood pressure lowering can be used to determine the dose of antihypertensive agent to administer to achieve a certain magnitude of blood pressure reduction. However, the astute clinician recognizes that ED₅₀ values are derived from the average of a great many patients and thus should be used only as initial guidelines. Because of interindividual variability, each patient may respond in ways that differ from the average. The second type of dose-response curves, quantal dose-response curves, provide an estimate of this variability.

Quantal Dose-Response Curves

Quantal dose-response curves do the following:

Quantify responses for variables that are all or none (e.g., seizure or no seizure).

Describe the relationship between drug dosage and the frequency with which a biologic effect occurs. For example, in individuals administered an anticonvulsant medication, the percentage of individuals not experiencing a convulsive episode at any given dose is plotted in cumulative fashion (Figure 1-2, B).

Represent a cumulative frequency distribution for a given response.

Provide an ED₅₀ value that reflects the dose of drug that produces a response in 50% of the population (also called the median effective dose).

Provide an E_max value that is the dose at which all of the patients respond to the drug.

Provide an estimate of the variability in response of the patient population to the drug. A steep slope indicates that all the patients respond in a narrow range of doses, whereas a shallow slope indicates considerable variability in the ability of the drug to elicit a response in the patient population.

Can be constructed for a graded or continuous response by choosing a target magnitude of response (e.g., blood pressure reduction of 20 mm Hg) and plotting the proportion of patients that achieves this magnitude of response at each increase in dosage. This type of information can be useful in determining a starting dosage to achieve a given level of effect

Can be plotted for therapeutic, toxic, and lethal effects to obtain:

• TD₅₀ (median toxic dose), is the dose that produces toxic effects in 50% of the patient population.

• LD₅₀ (median lethal dose), the dose at which 50% of patients die

• Comparison of these parameters can provide an estimate of the relative safety of treatment.

• Therapeutic index (TI) or therapeutic ratio is the ratio of the LD₅₀ and ED₅₀. Large values of TI are desirable because they indicate that the doses that produce death are much greater than those that produce a therapeutic effect.

• Therapeutic window is a loosely defined term that generally refers to the range of doses that produce therapeutic effects with minimal toxic effects. It can be viewed as the lack of overlap between the quantal dose-response curves for therapeutic and toxic or lethal effects. There are several indices of the degree of this overlap.

• Certain safety factor: The certain safety factor is the dose of drug that produces a lethal effect in 1% of the population (LD₁) divided by the dose that produces a therapeutic effect in 99% of the population (ED₉₉) (LD₁/ED₉₉).

• Protective index: The protective index is calculated as the dose for an undesirable effect in 50% of patients (TD₅₀) divided by the ED₅₀ for the desired effect (TD₅₀/ED₅₀).

• For both the certain safety factor and the protective index, large values signify that there is little overlap between the therapeutic and toxic or lethal effects of the drug, and thus there is a relatively large margin of safety for its use.